Phenethanolamine derivatives having β2 -adrenoreceptor selective stimulant action

ABSTRACT

Phenethanolamine derivatives are disclosed of formula ##STR1## wherein m is 2 to 8; n is 1 to 7 provided that m+n is 4 to 12; 
     Ar is phenyl or phenyl substituted by one or two halogen atoms, alkyl or alkoxy groups or by an alkylenedioxy group; 
     R 1  and R 2  are hydrogen or alkyl provided that the sum total of carbon atoms in R 1  and R 2  is not more than 4; 
     and the physiologically acceptable salts and solvates thereof. 
     The compounds have a selective stimulant action at β 2  -adrenoreceptors and may be used inter alia in the treatment of diseases associated with reversible airways obstructions such as asthma and chronic bronchitis. The compounds may be formulated in conventional manner as pharmaceutical compositions with physiologically acceptable carriers or excipients. 
     The compounds may be prepared, for example by alkylation of an amine: ##STR2## where R 3 , R 5  and R 6  is hydrogen or a protecting group, followed by removal of any protecting group.

This is a division of co-pending application Ser. No. 619,899 filed Nov.29, 1990, U.S. Pat. No. 5,126,375, which is a continuation of Ser. No.397,664 filed Aug. 23, 1989, U.S. Pat. No. 4,992,474, which is acontinuation of Ser. No. 932,359 filed on Nov. 19, 1986, abandoned,which is a continuation of Ser. No. 601,444 filed on Apr. 18, 1984,abandoned.

This invention relates to phenethanolamine compounds having a stimulantaction at β₂ -adrenoreceptors, to processes for their preparation, topharmaceutical compositions containing them and to their use inmedicine.

Certain phenethanolamine compounds are known to possess either stimulantor blocking actions at β-adrenoreceptors. For example, British PatentSpecification No. 1200886 describes a group of such phenethanolamines ofgeneral structure: ##STR3## where, inter alia, X₁ is hydroxyalkyl, R₁and R₂ is each a hydrogen atom, and R₃ is straight or branched C₁₋₆alkyl, aralkyl or aryloxyalkyl. One compound from within this particulargroup has been developed for clinical use. This is salbutamol [(α¹-tert-butylaminomothyl)-4-hydroxy-m-xylene-α¹,α³ -diol; X₁ =CH₂ OH, R₁=--H; R₂ =--H; R₃ =t-butyl, above] which at the present time is widelyprescribed for the treatment of conditions such as bronchial asthma andchronic bronchitis. The success of salbutamol devolves from its profileof action, in particular its potency, coupled with a selective stimulantaction at β₂ -adrenoreceptors.

All β₂ -stimulants currently used in clinical practice suffer from thedisadvantage that they have a relatively short duration of action whenadministered by inhalation. A β₂ -stimulant with a relatively longduration of action would therefore offer a significant advance in thetreatment of bronchial asthma and related disorders.

In a search for new β-stimulants with advantageous properties, we havenow found a novel group of phenethanolamine derivatives, which differstructurally from the group of compounds described in British PatentSpecification No. 1200886, and which in our tests have shown a potentselective stimulant action at β₂ -adrenoreceptors, and, in addition,have an advantageous profile of action.

Thus, the present invention provides compounds of the general formula(I) ##STR4## wherein m is an integer from 2 to 8 and

n is an integer from 1 to 7 with the proviso that the sum total of m+nis 4 to 12;

Ar represents a phenyl group optionally substituted by one or twosubstituents selected from halogen atoms, C₁₋₃ alkyl or C₁₋₃ alkoxygroups, or by an alkylenedioxy group of formula --O(CH₂)_(p) O-- where pis 1 or 2; and

R¹ and R² each represents a hydrogen atom or a C₁₋₃ alkyl group with theproviso that the sum total of carbon atoms in R¹ and R² is not more than4;

and physiologically acceptable salts and solvates (e.g. hydrates)thereof.

It will be appreciated that the compounds of general formula (I) possessone or two asymmetric carbon atoms, namely the carbon atom of the##STR5## group and, when R¹ and R² are different groups, the carbon atomto which these groups are attached.

The compounds according to the invention thus include all enantiomers,diastereoisomers and mixtures thereof, including racemates. Compounds inwhich the carbon atom in the ##STR6## group is in the R configurationare preferred.

In the general formula (I), the chain --(CH₂)_(m) -- may be, forexample, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₆ -- or --(CH₂)₇--, and the chain --(CH₂)_(n) -- may be, for example, --(CH₂)₂ --,--(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ -- or (CH₂)₆ --.

Preferably the sum total of the number of carbon atoms in the chains--(CH₂)_(m) -- and --(CH₂)_(n) is 6 to 12 inclusive and may be, forexample, 7, 8, 9 or 10. Compounds wherein the sum total of m+n is 7, 8or 9 are particularly preferred.

Preferred compounds of general formula (I) are those wherein m is 3 andn is 6, or m is 4 and n is 3, 4 or 5, or m is 5 and n is 2, 3, 4 or 5,or m is 6 and n is 2 or 3.

R¹ and R², for example, may each be methyl, ethyl, propyl, or isopropylgroups except that if one of R¹ and R² is a propyl or isopropyl group,the other is a hydrogen atom or a methyl group. Thus, for example, R¹may be a hydrogen atom or a methyl, ethyl or propyl group. R², forexample, may be a hydrogen atom or a methyl group.

R¹ and R² are each preferably a hydrogen atom or a methyl group.

A preferred group of compounds is that wherein R¹ and R² are bothhydrogen atoms. In another preferred group of compounds R¹ is a hydrogenatom and R² is a C₁₋₃ alkyl group, particularly a methyl group. In yetanother preferred group of compounds R¹ and R² are both methyl groups.

The chain ##STR7## in general formula (I) may be, for example --(CH₂)₄O(CH₂)₄ --, (CH₂)₅ O(CH₂)₂ -- --(CH₂)₅ O(CH₂)₃, --(CH₂)₅ O(CH₂)₄ --,##STR8## where R¹ is methyl, ethyl or propyl.

Examples of the optional substituents which may be present on the phenylgroup represented by Ar include bromine, iodine or, in particular,chlorine or fluorine atoms, or methyl, ethyl, methoxy or ethoxy groups.In general, Ar is preferably an unsubstituted phenyl group. According toanother preference, Ar is a phenyl group substituted by one substituent,particularly a fluorine or chlorine atom or a methoxy or methyl group.

Suitable physiologically acceptable salts of the compounds of generalformula (I) include acid addition salts derived from inorganic andorganic acids, such as hydrochlorides, hydrobromides, sulphates,phosphates, maleates, tartrates, citrates, benzoates,4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates,p-toluenesulphonates, methanesulphonates, ascorbates, salicylates,acetates, fumarates, succinates, lactates, glutarates, gluconates,tricarballylates, hydroxynaphthalenecarboxylates e.g. 1-hydroxy- or3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds may alsoform salts with suitable bases. Examples of such salts are alkali metal(e.g. sodium and potassium), and alkaline earth metal (e.g. calcium andmagnesium) salts.

The compounds according to the invention have a selective stimulantaction at β₂ -adrenoreceptors, which furthermore is of a particularlyadvantageous profile. The stimulant action was demonstrated in theguinea-pig, where compounds were shown to cause relaxation ofPGF2α-contracted isolated trachea. In another test, compounds of theinvention were shown to afford protection against histamine-inducedbroncho-constriction when administered by inhalation or by an oral routein conscious guinea-pigs. In both tests, compounds according theinvention have shown a particularly long duration of action. Theselective action of compounds of the invention was demonstrated in therat or guinea pig. Where compounds were shown to have little or noeffect on isolated rat or guinea pig left atria (β₁ -adrenoreceptortissues) at concentrations where they cause relaxation of PGF₂α-contracted isolated trachea. Compounds according to the invention havealso been shown to inhibit the anaphylactic release of spasmagens andinflammagens from sensitised human tissues e.g. lung fragments.

The compounds according to the invention may be used in the treatment ofdiseases associated with reversible airways obstruction such as asthmaand chronic bronchitis.

The compounds according to the invention may also be used for thetreatment of premature labour, depression and congestive heart failure,and are also indicated as useful for the treatment of inflammatory andallergic skin diseases, psoriasis, proliferative skin diseases,glaucoma, and in the treatment of conditions in which there is anadvantage in lowering gastric acidity, particularly in gastric andpeptic ulceration.

A particularly important group of compounds by virtue of theadvantageously long duration of action they have shown in our tests, hasthe formula (Ia): ##STR9## in which R¹ and R² are as defined for generalformula (I);

m is an integer from 3 to 6,

n is an integer from 2 to 6,

and Ar is phenyl or phenyl substituted by a methoxy or methyl group, ormore preferably a fluorine or chlorine atom, and the physiologicallyacceptable salts and solvates thereof, in each instance the sum total ofcarbon atoms in the chains --(CH₂)_(m) -- and --(CH₂)_(n) -- being aninteger from 7 to 10 inclusive, in particular 7, 8 or 9.

A preferred group of compounds of formula (Ia) is that wherein R¹ and R²is each a hydrogen atom.

In another preferred group of compounds of formula (Ia) R¹ is a hydrogenatom or a methyl group and R² is a methyl group.

In a further group of compounds of formula (Ia) R¹ and R² each is ahydrogen atom and Ar is phenyl or phenyl substituted by a methoxy group,or more preferably a fluorine or chlorine atom.

A particularly preferred group of compounds has the formula (Ia) inwhich R¹ and R² each is a hydrogen atom or a methyl group, m is 4 or 5,n is 2, 3 or 4, and Ar is phenyl or phenyl substituted by a chlorine orfluorine atom or a methoxy or methyl group and the physiologicallyacceptable salts and solvates thereof.

Particularly important compounds are:

4-hydroxy-α¹[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol; and thephysiologically acceptable salts thereof;

4-hydroxy-α¹[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol; and thephysiologically acceptable salts thereof;

4-hydroxy-α¹-[[[6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol; and thephysiologically acceptable salts thereof;

4-hydroxy-α¹-[[[5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol; andthe physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[1-methyl-6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[1-methyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[1-methyl-5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[1-ethyl-6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

α¹-[[[1,1-dimethyl-6-(2-phenylethoxy)hexyl]amino]methyl-4-hydroxy-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

α¹-[[[6-[2-(4-fluorophenyl)ethoxy]-1-methylhexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[6-[3-(4-methoxyphenyl)propoxy]-1-methylhexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[1-methyl-6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[6-[2-(4-methylphenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

α¹-[[[6-[2-(3-chlorophenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

4-hydroxy-α¹-[[[6-[2-(4-methoxyphenyl)ethoxy]hexyl]-amino]-methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof;

α¹-[[[6-[3-(4-fluorophenyl)propoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol;and the physiologically acceptable salts thereof.

The invention accordingly further provides compounds of formula (I) andtheir physiologically acceptable salts and solvates for use in thetherapy or prophylaxis of diseases associated with reversible airwaysobstruction in human or animal subjects. The invention also providescompounds of formula (I) and their physiologically acceptable salts andsolvates and compositions containing them in association withinstructions for their use in the therapy or prophylaxis of diseasesassociated with reversible airways obstruction in human or animalsubjects.

The compounds according to the invention may be formulated foradministration in any convenient way. The invention therefore includeswithin its scope pharmaceutical compositions comprising at least onecompound of formula (I) or a physiologically acceptable salt or solvatethereof formulated for use in human or veterinary medicine. Suchcompositions may be presented for use with physiologically acceptablecarriers or excipients, optionally with supplementary medicinal agents.

The compounds may be formulated in a form suitable for administration byinhalation or insufflation, or for oral, buccal, parenteral, topical(including nasal) or rectal administration. Administration by inhalationor insufflation is preferred.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs, with the use of a suitablepropellent, such as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or froma nebuliser. In the case of a pressurised aerosol the dosage unit may bedetermined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form in, for example, capsules or cartridges ofe.g. gelatin, or blister packs from which the powder may be administeredwith the aid of an inhaler or insufflator.

For oral administration, the pharmaceutical composition may take theform of, for example, tablets, capsules, powders, solutions, syrups orsuspensions prepared by conventional means with acceptable excipients.

For buccal administration the composition may take the form of tablets,drops or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration. Formulations for injections may be presented in unitdosage form in ampoules, or in multi-dose containers with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forreconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

For topical administration the pharmaceutical composition may take theform of ointments, lotions or creams formulated in a conventionalmanner, with for example an aqueous or oily base, generally with theaddition of suitable thickening agents and/or solvents. For nasalapplication, the composition may take the form of a spray, formulatedfor example as an aqueous solution or suspension or as an aerosol withthe use of a suitable propellant.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glyceride.

Where pharmaceutical compositions are described above for oral, buccal,rectal or topical administration, these may be presented in aconventional manner associated with controlled release forms.

A proposed daily dosage of active compound for the treatment of man is0.0005 mg to 100 mg, which may be conveniently administered in one ortwo doses. The precise dose employed will of course depend on the ageand condition of the patient and on the route of administration. Thus asuitable dose for administration by inhalation is 0.0005 mg to 10 mg,for oral administration is 0.02 mg to 100 mg, and for parenteraladministration is 0.001 mg to 2 mg.

The compounds according to the invention may be prepared by a number ofprocesses, as described in the following wherein m, n, Ar, R¹ and R² areas defined for general formula (I) unless otherwise specified. In thegeneral processes (1) to (3) described below the final step in thereaction may be the removal of a protecting group. Suitable protectinggroups and their removal are described in general process (4) below.

According to one general process (1), a compound of general formula (I)may be prepared by alkylation. Conventional alkylation procedures may beused.

Thus, for example, in one process (a), a compound of general formula (I)in which R¹ is a hydrogen atom may be prepared by alkylation of an amineof general formula (II): ##STR10## (wherein R³, R⁵ and R⁶ each is ahydrogen atom or a protecting group and R⁴ is a hydrogen atom) followedby removal of any protecting group where present.

The alkylating reaction (a) may be effected using an alkylating agent ofgeneral formula (III): ##STR11## (wherein L represents a leaving group,for example a halogen atom such as chlorine, bromine or iodine, or ahydrocarbylsulphonyloxy group such as methanesulphonyloxy orp-toluenesulphonyloxy).

The alkylation is preferably effected in the presence of a suitable acidscavenger, for example, inorganic bases such as sodium or potassiumcarbonate, organic bases such as triethylamine, diisopropylethylamine orpyridine, or alkylene oxides such as ethylene oxide or propylene oxide.The reaction is conveniently effected in a solvent such as acetonitrileor an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone ormethyl isobutyl ketone, a substituted amide e.g. dimethylformamide or achlorinated hydrocarbon e.g. chloroform at a temperature between ambientand the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound ofgeneral formula (I) in which R¹ represents a hydrogen atom may beprepared by alkylation of an amine of general formula (II), aspreviously defined except that R⁴ is a hydrogen atom or a groupconvertible thereto under the reaction conditions, with a compound ofgeneral formula (IV):

    R.sup.2 CO(CH.sub.2).sub.m --O--(CH.sub.2).sub.n Ar        (IV)

in the presence of a reducing agent, followed when necessary by removalof any protecting groups.

Examples of suitable groups represented by R⁴ which are convertible intoa hydrogen atom are arylmethyl groups such as benzyl, α-methyl benzyland benzhydryl.

Suitable reducing agents include hydrogen in the presence of a metalcatalyst such as platinum, platinum oxide, palladium, Raney nickel orrhodium, on a support, such as charcoal, using an alcohol, e.g. ethanolor an ester e.g. ethyl acetate or an ether e.g. tetrahydrofuran, orwater, as reaction solvent, or a mixture of solvents, e.g. a mixture oftwo or more of those just described, at normal or elevated temperatureand pressure, for example from 20° to 100° C. and from 1 to 10atmospheres.

Alternatively when one or both of R³ and R⁴ are hydrogen atoms, thereducing agent may be a hydride such as diborane or a metal hydride suchas sodium borohydride, sodium cyanoborohydride or lithium aluminiumhydride. Suitable solvents for the reaction with these reducing agentswill depend on the particular hydride used, but will include alcoholssuch as methanol or ethanol, or ethers such as diethyl ether ortert-butyl methyl ether, or tetrahydrofuran.

When a compound of formula (II) wherein R³ and R⁴ are both hydrogenatoms is used, the intermediate imine of formula (V) may be formed:##STR12## (wherein R⁶ and R⁵ are as defined for formula (II)).

Reduction of the imine using the conditions described above, followed,where necessary, by removal of any protecting groups, gives a compoundof general formula (I).

Where it is desired to use a protected intermediate of general formula(II) it is particularly convenient to use hydrogen and a metal catalystas described above with protecting groups R³, R⁵ and R⁶ which arecapable of being converted to a hydrogen atom under these reducingconditions, thus avoiding the need for a separate deprotection step.Suitable protecting groups of this type include arylmethyl groups suchas benzyl, benzhydryl and α-methylbenzyl.

In a second general process (2), a compound of general formula (I) maybe prepared by reduction. Thus, for example, a compound of generalformula (I) may be prepared by reducing an intermediate of generalformula (VI): ##STR13## (wherein R⁵ is as defined for general formula(II) and at least one of X, X¹, X², X³ and X⁴ represents a reduciblegroup and the other(s) take the appropriate meaning as follows, which isX is CH₂ OR⁶, X¹ is --CH(OH)--, X² is --CH₂ NR³, X³ is --CR¹ R²(CH₂)_(m-1) -- and X⁴ is --(CH₂)_(n-1) --) followed where necessary byremoval of any protecting groups.

Suitable reducible groups include those wherein X is a group --CO₂ R⁷(wherein R⁷ represents a hydrogen atom, or an alkyl, aryl or aralkylgroup) or --CHO, X¹ is a group --C═0, X² is a group --CH₂ NY-- (whereinY represents a group convertible to hydrogen by catalytic hydrogenation,for example an arylmethyl group such as benzyl, benzhydryl orα-methylbenzyl), or an imine (--CH═N--) group or a group --CONH--, andX³ is a group --CO(CH₂)_(m-1) --, or a group --CR¹ R² X⁵ -- where X⁵ isC₂₋₇ alkenylene or C₂₋₇ alkynylene, or X² --X³ -- is a group --CH₂ N═CR²(CH₂)_(m-1), and X⁴ is C₂₋₆ alkenylene or C₂₋₆ alkynylene. In oneconvenient aspect of the reduction process, the group R⁵ may be a groupconvertible to hydrogen under the reducing conditions employed and maybe for example an arylmethyl group such as benzyl, benzhydryl orα-methylbenzyl.

The reduction may be effected using reducing agents convenientlyemployed for the reduction of carboxylic acids, aldehydes, esters,ketones, imines, amides, ethylenes, acetylenes and protected amines.Thus, for example, when X in general formula (VI) represents a group--CO₂ R⁷ or --CHO this may be reduced to a group --CH₂ OH using ahydride such as diborane or a complex metal hydride such as lithiumaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, sodiumborohydride, diisobutylaluminium hydride or lithium triethylborohydridein a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether, ora halogenated hydrocarbon e.g. dichloromethane at a temperature from 0°C. to the reflux.

When X¹ in general formula (VI) represents a --C═0 group this may bereduced to a --CH(OH)-- group using hydrogen in the presence of a metalcatalyst as previously described for process (1) part (b).Alternatively, the reducing agent may be, for example, a hydride such asdiborane or a metal hydride such as lithium aluminium hydride, sodiumbis(2-methoxyethoxy) aluminium hydride, sodium borohydride or aluminiumhydride. The reaction may be effected in a solvent, where appropriate analcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran,or a halogenated hydrocarbon such as dichloromethane.

When X² in general formula (VI) represents a CH₂ NY group or the group--CH═N--, or --X² --X³ represents --CH₂ N═CR² (CH₂)_(m-1) this may bereduced to a --CH₂ NH-- or --CH₂ NHCHR² (CH₂)_(m-1) group using hydrogenin the presence of a metal catalyst as previously described for process(1) part (b). Alternatively, when X² or --X² --X³ is the group --CH═N--or --CH₂ N═CR² (CH₂)_(m-1) this may be reduced to a --CH₂ NH-- or CH₂NHCHR₂ (CH₂)_(m-1) group using a reducing agent and conditions as justdescribed for the reduction of X¹ when this represents a --C═O group.

When X² or X³ in general formula (VI) represents a --CONH-- or--CO(CH₂)_(m-1) -- group this may be reduced to a group --CH₂ NH-- or--CH₂ (CH₂)_(m-1) -- using a hydride such as diborane or a complex metalhydride such as lithium aluminium hydride or sodiumbis(2-methoxyethoxy)aluminium hydride in a solvent such as an ether,e.g.-tetrahydrofuran or diethyl ether.

When X³ in general formula (VI) represents a group --CR¹ R² X⁵ -- thismay be reduced to a group --CR¹ R² (CH₂)_(m-1) -- using hydrogen in thepresence of a catalyst such as platinum or palladium on a support suchas charcoal in a solvent such as an alcohol, e.g. ethanol or methanol,or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, atnormal or elevated temperature and pressure.

When X⁴ is C₂₋₆ alkenylene or C₂₋₆ alkynylene this may be reduced to--(CH₂)_(n-1) -- using hydrogen and a catalyst as just described. Inthis aspect of the reduction process, suitable starting materials offormula (VI) include those in which CR¹ R² X⁵ and/or X⁴ each containsone --C═C-- or --C.tbd.C-- linkage. Where both contain unsaturatedlinkages, these may be the same or different.

Particular examples of the reduction process are those in which acompound of general formula (I) in which --(CH₂)_(m) -- represents--(CH₂)₅ -- is prepared from a corresponding compound in which--(CH₂)_(m) -- represents --CH═CH(CH₂)₃ --, --C.tbd.C(CH₂)₃ --, --(CH₂)₂CH═CHCH₂ -- or --(CH₂)₂ C.tbd.CCH₂ --. In further examples, a compoundof general formula (I) in which --(CH₂)_(n) -- represents --(CH₂)₄ -- or--(CH₂)₃ -- may be prepared by reduction of a corresponding compound ofgeneral formula (I) in which --(CH₂)_(n) -- represents --CH₂ CH═CH--CH₂,--CH₂ C.tbd.CCH₂, --CH₂ CH₂ CH═CH--, --CH₂ CH₂ C.tbd.C--, --CH₂ CH═CH or--CH₂ C.tbd.C--.

In the reduction processes just described the groups X and R⁵ in acompound of formula (VI) may together conveniently represent a group##STR14## (where R⁸ and R⁹, which may be the same or different, eachrepresents a hydrogen atom or an alkyl or aryl group. After thereduction is complete, cleavage of this group using e.g. a dilute acidin a solvent such as water at normal temperature yields a compound offormula (I).

According to a further general process (3), a compound of generalformula (I) may be obtained by reaction of a compound of general formula(VII): ##STR15## (wherein Z represents a group ##STR16## and L, R⁵ andR⁶ are as previously defined, with an amine of general formula (VIII):##STR17## (wherein Y¹ is a hydrogen atom or a group convertible theretoby catalytic hydrogenation) followed by removal of any protecting groupswhere present, as described hereinafter.

Suitable Y¹ groups convertible into a hydrogen atom include arylmethylgroups such as benzyl, benzhydryl or α-methylbenzyl.

The reaction may be effected in the presence of a suitable solvent forexample an alcohol, such as ethanol, a halogenated hydrocarbon e.g.chloroform, a substituted amide e.g. dimethylformamide or an ether suchas tetrahydrofuran or dioxan at a temperature from ambient to thereflux, optionally in the presence of a base such as an organic aminee.g. diisopropylethylamine or an inorganic base such as sodiumcarbonate.

The intermediate amines of general formula (VIII) and their acidaddition salts are novel compounds and form a further aspect of theinvention. A particularly preferred group of amines of general formula(VIII) are those in which the total number of carbon atoms in the groupsrepresented by ##STR18## and (CH₂)_(n) is from 7 to 13 inclusive.

In another general process (4), a compound of general formula (I) may beobtained by deprotection of a protected intermediate of general formula(IX): ##STR19## (wherein R³, R⁵ and R⁶ are as previously defined exceptthat at least one of R³, R⁵ and R⁶ is a protecting group).

The protecting group may be any conventional protecting group, forexample as described in "Protective Groups in Organic Chemistry", Ed. J.F. W. McOmie (Plenum Press, 1973). Examples of suitable hydroxylprotecting groups represented by R⁵ and R⁶ are aralkyl groups such asbenzyl, diphenylmethyl or triphenylmethyl, and tetrahydropyranyl.Examples of suitable amino protecting groups represented by R³ arearalkyl groups such as benzyl, α-methylbenzyl, diphenylmethyl ortriphenylmethyl and acyl groups such as trichloroacetyl ortrifluoroacetyl.

The deprotection to yield a compound of general formula (I) may beeffected using conventional techniques. Thus, for example, when R⁵, R⁶and/or R³ is an aralkyl group this may be cleaved by hydrogenolysis inthe presence of a metal catalyst (e.g. palladium on charcoal). When R⁵and/or R⁶ is tetrahydropyranyl this may be cleaved by hydrolysis underacidic conditions. Acyl groups represented by R³ may be removed byhydrolysis, for example with a base such as sodium hydroxide, or a groupsuch as trichloroacetyl, or trifluoroacetyl may be removed by reductionwith, for example, zinc and acetic acid.

In a particular embodiment of the deprotection process (4), R⁵ and R⁶may together represent a protecting group as in a compound of generalformula (X): ##STR20## (wherein R⁸ and R⁹ are as previously defined).

A compound of general formula (I) may be obtained by treatment of acompound of formula (X) with a dilute acid, for example hydrochloricacid in a solvent such as water or an alcohol such as ethanol at normalor elevated temperature.

In the general processes (1) to (4) described above, the compound offormula (I) obtained may be in the form of a salt, conveniently in theform of a physiologically acceptable salt. Where desired such salts maybe converted to the corresponding free base using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I)may be prepared by reacting a compound of general formula (I) with anappropriate acid or base in the presence of a suitable solvent such asacetonitrile, acetone, chloroform, ethyl acetate or an alcohol e.g.methanol, ethanol or iso-propanol.

Physiologically acceptable salts may also be prepared from other salts,including other physiologically acceptable salts, of the compounds ofgeneral formula (I), using conventional methods.

When a specific enantiomer of a compound of general formula (I)possessing one asymmetric carbon atom is required, this may be obtainedby resolution of a mixture of enantiomers of a corresponding compound ofgeneral formula (I) using conventional methods.

Thus, in one example an appropriate optically active acid may be used toform salts with a mixture of enantiomers of a compound of generalformula (I). The resulting mixture of isomeric salts may be separated,for example by fractional crystallisation, into the diastereoisomericsalts from which the required enantiomer of a compound of generalformula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I)possessing one asymmetric carbon atom may be synthesised from theappropriate optically active intermediates using any of the generalprocesses described herein.

When a compound of formula (I) contains two asymmetric carbon atoms,specific diasteroisomers or enantiomers thereof may be obtained from anappropriate asymmetric starting material or by separation of anappropriate mixture of isomers using techniques just described.

Suitable methods for preparing the intermediate compounds used in theabove general processes are described below. In the followingdiscussion, Ar, m, n, R¹, R², R³, R⁴, Y and Y¹, Z, X, X¹, X², X³ and Lare as defined above except where otherwise indicated. "Hal" representsa halogen atom. Where an intermediate with protected hydroxyl and/oramino groups is desired, this may be obtained using conventionalprotection methods, for example those described by McOmie (see process(4) above).

The intermediate compounds of general formula (III) may be prepared byreaction of an alcohol of general formula (XI):

    Ar(CH.sub.2).sub.n OH                                      (XI)

with a disubstituted alkane of general formula (XII):

    LCH.sub.2 (CH.sub.2).sub.m L.sup.1                         (XII)

(wherein L¹ is as previously defined for L, and L and L¹ may be the sameor different), optionally in a solvent such as tetrahydrofuran ordimethylformamide at a temperature up to the boiling point. The reactionis effected by first generating the anion of the alcohol of generalformula (XI) by adding for example sodium, sodium hydride or a strongbase such as sodium hydroxide and a phase transfer catalyst such astetrabutylammonium sulphate. Optionally a solvent such asdichloromethane or tetrahydrofuran may be added. The reaction can becarried out at ambient or elevated temperatures.

The compounds of general formulae (XI) and (XII) are either knowncompounds or they may be made by methods analogous to those used for thepreparation of the known compounds.

Intermediate aldehydes of general formula (IV) (in which R² represents ahydrogen atom) may be prepared by oxidation of an alcohol of generalformula (XIII):

    Ar(CH.sub.2).sub.n O(CH.sub.2).sub.m CH.sub.2 OH           (XIII)

with an oxidising agent such as pyridinium chlorochromate in a solventsuch as a halogenated hydrocarbon, e.g. dichloromethane. The alcohols offormula (XIII) may be prepared from the compounds of formula (III), forexample by reaction with sodium acetate, followed by hydrolysis of theproduct with for example sodium hydroxide.

Intermediate ketones of formula (IV) (in which R² represents an alkylgroup), may be prepared by reaction of a Grignard complex of a halide offormula (XIV):

    Ar(CH.sub.2).sub.n O(CH.sub.2).sub.m Hal                   (XIV)

with an acyl halide R² COCl or anhydride (R² CO)₂ O in a solvent such asan ether, for example diethyl ether or tetrahydrofuran. The halides offormula (XIV) may be prepared by alkylation of an alcohol of formula(XI) with a disubstituted alkane of formula L(CH₂)_(m) Hal as describedabove for the preparation of compounds of formula (III). CompoundsL(CH₂)_(m) Hal are either known compounds or they may be made by methodsanalogous to those used for preparation of the known compounds.

Intermediate compounds of general formula (VI) for use in generalprocess (2) may be prepared by a number of processes.

Thus for example intermediates of general formula (VI) in which X¹ is agroup --C═O may be prepared from a haloketone of formula (XV): ##STR21##by reaction with an amine of general formula (VIII). The reaction may beeffected in a cold or hot solvent, for example tetrahydrofuran,tert-butyl methyl ether, dioxan, chloroform, dimethylformamide,acetonitrile or a ketone such as butanone or methylisobutylketone, or anester, for example ethyl acetate preferably in the presence of a basesuch as diisopropylethylamine, sodium carbonate or other acid scavengersuch as propylene oxide. When --(CH₂)_(m) and/or --(CH₂)_(n) -- in theamine of formula (VIII) contains an unsaturated linkage, an intermediateof formula (VI) in which X³ is --CR¹ R² X⁵ -- and/or X⁴ is C₂₋₆alkenylene or C₂₋₆ alkynylene may be obtained in this process.

Intermediates of general formula (VI) in which X¹ is a group --C═O maybe reduced to the corresponding intermediate in which X¹ is a group--CH(OH)-- using for example a metal hydride such as sodium borohydridein a solvent e.g. ethanol.

Iminoketones of general formula (VI) i.e. in which X² is a group--CH═N-- may be obtained from a phenylglyoxal derivative of formula(XVI): ##STR22## by reaction with an amine of formula (VIII) in which Y¹represents a hydrogen atom, in a solvent such as benzene,tetrahydrofuran or an alcohol e.g. ethanol at temperatures up to thereflux. The phenylglyoxal derivatives of formula (XVI) may be obtainedfrom a haloketone of formula (XV) by the action of a dialkylsulphoxidesuch as dimethylsulphoxide.

When X and R⁵ in the glyoxal of formula (XVI) together represent a group##STR23## the iminoketone of formula (VI) so formed using this processsubsequently may be reduced using a metal hydride such as sodiumborohydride in a solvent such as ethanol to yield a compound of formula(X).

Intermediates of general formula (VI) in which X³ is a group--CO(CH₂)_(m) -- may be prepared by acylation of an amine of formula(XVII): ##STR24## using an ester or an activated derivative of an acidof formula (XVIII):

    Ar(CH.sub.2).sub.n O(CH.sub.2).sub.m CO.sub.2 H            (XVIII)

Suitable activated derivatives include the acid chloride, an anhydrideor imidazolide. The reaction may be optionally carried out in a solventsuch as tetrahydrofuran, benzene or chloroform, optionally in thepresence of a base such as pyridine or triethylamine. The acids (XVIII)may be used directly if a coupling agent such asdicyclohexylcarbodiimide is added.

Acids of formula (XVIII) may be obtained by treatment of an alcohol ofgeneral formula (XIII) with a suitable oxidising agent, for examplepyridinium dichromate in a solvent such as dimethylformamide.

Intermediates of formula (VI) in which --X² --X³ -- represents --CH₂N═CR² (CH₂)_(m-1) may be obtained by reaction of an amine of formula(XVII) in which R³ is a hydrogen atom with a compound of formula (IV)preferably in a solvent such as acetonitrile.

Intermediates of formula (VI) in which X² is --CONH-- may be prepared byreaction of an amine of formula (VIII) with an acid of formula (XIX)##STR25## in the presence of a coupling agent such asdicyclohexylcarbodiimide.

Compounds of formula (VII) in which X represents a group ##STR26## maybe prepared from a haloketone of formula (XX): ##STR27## by reductionusing for example a metal hydride such as sodium borohydride in asolvent such as ethanol.

The halogen atom may be displaced to yield other compounds of generalformula (VII) in which Z is a group ##STR28## where L is a leaving groupother than a halogen atom.

Compounds of formula (VII) wherein Z represents ##STR29## may beprepared from the corresponding compound in which Z is ##STR30## bytreatment with a base, for example an amine, which may be for example acompound of general formula (VIII), or an inorganic base such as sodiumhydroxide in a solvent such as ethanol.

The amines of general formula (VIII) in which Y¹ is a group convertibleto hydrogen and R¹ and R² are both hydrogen atoms may be prepared byreaction of a compound of general formula (III) in which R² is ahydrogen atom with an amine YNH₂. The reaction may be effected in theabsence or presence of a solvent such as a ketone e.g. butanone ormethyl isobutyl ketone, an ether e.g. tetrahydrofuran or a substitutedamide e.g. dimethylformamide, optionally in the presence of a base suchas sodium carbonate or an organic amine e.g. triethylamine orN,N-diisopropylethylamine at temperatures between 0° C. and the reflux.Where desired, subsequent reaction with hydrogen in the presence of ametal catalyst such as platinum in a solvent such as an alcohol e.g.ethanol yields a compound of formula (VIII) where Y¹ is a hydrogen atom.

Alternatively, amines of formula (VIII) in which R¹ is a hydrogen atommay be prepared by reductive alkylation of an amine Y¹ NH₂, in which Y¹is a group convertible into hydrogen with a compound of formula (IV), ifnecessary followed by conversion of the Y¹ group to a hydrogen atom asjust described.

The reaction may be effected by hydrogen in the absence or presence of asolvent such as an alcohol, e.g. ethanol with a metal catalyst such asplatinum or palladium, or by use of a complex metal hydride such assodium borohydride or sodium cyanoborohydride in an alcohol, forexample, ethanol.

A process to afford amines of formula (VIII) in which R¹ and R² can bothbe alkyl groups uses an acid of formula (XXI): ##STR31##

The acid is converted via its chloride and azide by a Curtius reactioninto the amine of formula (VIII) in which Y¹ is a hydrogen atom. Thereaction involves thermal rearrangement of the azide into an isocyanate,which is hydrolysed by treatment with an inorganic base, for exampleaqueous sodium hydroxide optionally in a solvent such as ethanol.

The acids of formula (XXI) can be prepared by alkylation of the acid(XXII): ##STR32## via its dilithio derivative with an alkylating agentof formula (XIV) in a solvent such as an ether, for exampletetrahydrofuran at low temperature such as 0° C. to ambient.

The compounds of formulae (II), (IV), (XVII), (XIX), (XX), (XXI) and(XXII) are either known compounds or may be obtained by analogousmethods to those used for the preparation of the known compounds.

The following examples illustrate the invention.

Temperatures are in °C. Thin layer chromatography (T.l.c.) was carriedout over SiO₂ and `dried` refers to drying using magnesium sulphate,except where otherwise stated.

The following abbreviations are used: DMF--dimethylformamide;THF--tetrahydrofuran; EA--ethyl acetate; ER--diethyl ether;CX--cyclohexane; HX--hexane; BR--brine; flash column chromatography[FCS]--on silica [FCTS]--on triethylamine-deactivated silica;T.l.c.EN--t.l.c. over triethylamine-deactivated SiO₂.

Eluants used for chromatography and t.l.c. are: [A]--CX-ER(19:1);[B]--CX-ER(9:1); [C]--ER-CX-triethylamine (60:40:1); [D]--CX-ER(1:4);[E]--CX-EA(19:1); [F]--CX-ER(4:1); [G]--ER; [H]--EA;[I]--EA-methanol-triethylamine(9:1:0.1); [J]--CX-ER(7:3);[K]--CX-EA(9:1); [L]--CX-ER(3:1); [M]--EA-CH₃ OH--NH₃ (9:1:0.1);[N]--EA-CH₃ OH(9:1); [O]--CX-ER(1:1).

Intermediate 1 is α¹ -(aminomethyl)-4-hydroxy-1,3-benzenedimethanol.

Intermediate 2 [2-[(6-Bromohexyl)oxy]ethyl]benzene

A mixture of phenethyl alcohol (20 g), 1,6-dibromohexane (195 g) andtetrabutylammonium bisulphate (3.0 g) in 50% w/v NaOH solution (100 ml)was heated at 65°-70° for 4h. The cooled reaction mixture was pouredinto H₂ O (400 ml) and extracted with CX (2×300 ml). The dried extractswere evaporated in vacuo to give a yellow liquid which was purified bydistillation under reduced pressure to give the title compound as acolourless liquid (26 g) b.p. 110°/0.1 mm. T.l.c. (EA) Rf 0.62.

Intermediate 3 [4-[(6-Bromohexyl)oxy]butyl]benzene

NaH (46% dispersion in oil; 6.5 g) was added portionwise to a solutionof 4-phenyl-1-butanol (15.0 g) and 1,6-dibromohexane (48.8 g) in THF(200 ml) under nitrogen. The resulting suspension was refluxed for 27hand treated with H₂ O (80 ml). The mixture was extracted with ER (2×200ml) and the dried extract was evaporated to leave an orange oil. The oilwas purified on a column of silica (800 ml) [A] to give a yellow oilwhich on distillation gave the title compound as a colourless oil (15.0g) b.p. 90°-95°/0.1 mmHg.

Intermediate 4 is α¹-[[bis(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol.

Intermediate 5 6-(4-Phenylbutoxy)hexan-1-ol

A mixture of Intermediate 3 (10 g) sodium acetate trihydrate (34.8 g),H₂ O (25 ml) and trioctylpropyl NH₄ Cl (2 g) was stirred vigorously on asteam bath for 2.5 h. 2M NaOH (50 ml) and ethanol (50 ml) were added tothe cooled mixture which was then stirred at RT for 30 min. The mixturewas diluted with BR (200 ml), extracted with ER and the organic phasewashed with H₂ O (200 ml), BR (200 ml), dried and evaporated underreduced pressure to give the title alcohol as a yellow oil, (7.16 g).T.l.c. [G] Rf 0.73.

Intermediate 6 6-(4-Phenylbutoxy)hexanal

Pyridinium chlorochromate (4.1 g) was added to a solution ofIntermediate 5 (3 g) in CH₂ Cl₂ (25 ml). The mixture was stirred at RTfor 0.75 h, triturated with ER (75 ml), and filtered through hyflo. Thefiltrate was evaporated and the residue dissolved in ER (50 ml),filtered through silica and evaporated under reduced pressure to give apale yellow oil. Purification by [FCS] (120 g) [B] gave the titlecompound as a colourless oil (1.65 g). T.l.c. [B] Rf 0.3.

Intermediate 7 N-[6-(4-Phenylbutoxy)hexyl]benzenemethanamine

A solution of benzylamine (16.64 g) and Intermediate 3 (11.27 g) in THF(45 ml) was kept at RT for 4 days, diluted with ER (450 ml), filteredand the filtrate evaporated to give a colourless oil which was purifiedby [FCS] [C] to give the title compound (9.94 g) as a colourless oil.

Analysis Found: C,81.60;H,10.1;N,4.2. C₂₃ H₃₃ NO requires

C,81.35;H,9.80;N,4.15%.

Intermediate 81-[4-Hydroxy-3-(hydroxymethyl)phenyl]-2-[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]ethanone

A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (1g), Intermediate 7, (1.4 g) and N,N-diisopropylethylamine (0.8 g) in THF(10 ml) was kept at 23° for 3 days. The mixture was diluted with ER (60ml), washed with 8% NaHCO₃ (50 ml) and BR (50 ml), dried and evaporatedin vacuo to give an oil. Purification by [FCS] (40 g) [D] afforded thetitle compound as a viscous yellow oil (1.68 g). T.l.c. [D] Rf 0.42.

Intermediate 9 2-Bromo-1-(2,2-dimethyl-1,3-benzodioxan-6-yl)ethanone

2-Methoxypropene (10 g) was added over 15 min to a stirred solution of2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (5 g) andtoluene-4-sulphonic acid (0.5 g) in CH₂ Cl₂ (100 ml) at 23°. The mixturewas stirred for 3 h, filtered through a was of triethylamine-deactivatedsilica and evaporated to give an oil. Purification by [FCTS] (300 g) [E]afforded the title compound as an oil (4.8 g) which solidified oncooling. A small sample was crystallised from light petroleum (b.p.60°-80°) to give white crystals m.p. 47°-48°.

Intermediate 101-(2,2-Dimethyl-1,3-benzodioxan-6-yl)-2-[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]ethanone

A solution of Intermediate 9 (1.6 g), Intermediate 7 (2.1 g) andN,N-diisopropylethylamine (1.2g) in THF (15 ml) was kept at 23° for 2days. The mixture was diluted with EA (80 ml) washed with 8% NaHCO₃ (50ml) and BR (50 ml), dried (Na₂ SO₄) and evaporated in vacuo to give ayellow oil. Purification by [FCS] (150 g) [F] gave the title compound asa pale-yellow oil (2.2 g). T.l.c. [F]Rf 0.27.

Intermediate 11 6-(4-Phenylbutoxy)hexanoic acid

A mixture of Intermediate 5 (4 g) and pyridinium dichromate (21.04 g) inDMF (50 ml) was stirred at RT for 15 h, diluted with H₂ O (300 ml) andextracted with ER (2×100 ml). The extract was washed with H₂ O (2×250ml), dried, filtered through a bed of silica and evaporated in vacuo togive a colourless oil. Purification by [FCS] (80 g) [F] gave the titlecompound as a colourless oil (0.85 g). T.l.c. [F] Rf 0.27.

Intermediate 12N-[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]-1-(4-phenylbutoxy)hexanamide

DMF (0.003 ml) and thionyl chloride (0.51 ml) were added to a solutionof Intermediate 11 (0.89 g) in dry CH₂ Cl₂ (17 ml). The resultantsolution was stirred at RT for 2.5 h and evaporated to dryness to givethe acid chloride. Intermediate 1 (0.934 g) in THF was treated withethyl (trimethylsilyl)acetate (3.57 ml). Tetrabutyl ammonium fluoride(0.9 ml) was added dropwise to the stirred suspension at 0°. Theresulting solution was stirred at RT for 2 h and added to a solution ofthe above acid chloride in THF (10 ml) under an atmosphere of nitrogen.Triethylamine (3.4 ml) was then added and the solution stirred at RT for4 h, left to stand overnight, added to 2N hydrochloric acid (30 ml) andstirred for 15 min. The product was extracted into EA (3×25 ml) theextracts were washed with H₂ O (25 ml), 8% NaHCO₃ solution (25 ml) andBR (25 ml). The dried (Na₂ SO₄) organic layer was evaporated to drynessto give a brown oil which was chromatographed on silica (Merck art 7754,40 g) [H] to give a pale yellow oil. The dried oil solidified to givethe title amide as an off white solid (1.06 g), m.p. 96°-97.5°.

Intermediate 13 6-(4-Phenylbutoxy)hexanamine

Intermediate 7 (25 g) in absolute ethanol (250 ml) was hydrogenated overpalladium on carbon (1 g) and platinum on carbon (1 g) catalysts. Themixture was filtered through Hyflo and evaporated under reduced pressureto give the title amine as a colourless oil (16.49 g). T.l.c. EN(CH₃ OH)Rf 0.3.

Intermediate 14 Methyl2-hydroxy-5-[[[6-(4-phenylbutoxy)hexyl]imino]acetyl]benzoate

A solution of Intermediate 13 (0.49 g) in methanol (5 ml) was added over15 min to a stirred suspension of methyl5-(dihydroxyacetyl)-2-hydroxybenzoate in methanol (10 ml) at 23°. Themixture was stirred for 10 min, evaporated in vacuo and the residuepurified by [FCTS] (40 g) [G] to give the title imine as a dark-orangeoil (0.61 g). The imine was unstable and should be used promptly afterpreparation. T.l.c. EN[G] Rf 0.37.

Intermediate 15α-(Bromomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-6-methanol

NaBH₄ (0.1 g) was added to a stirred solution of Intermediate 9 (0.6 g)in ethanol (20 ml) at 0°. The mixture was stirred at 0° for 1 h, dilutedwith H₂ O (50 ml) and extracted with EA (2×25 ml). The extract waswashed with BR (25 ml) dried and evaporated to give an oil which ontrituration with HX afforded the title bromohydrin as a white solid(0.55 g) m.p. 84°-85° unchanged on recrystallisation from HX.

Intermediate 16 2,2-Dimethyl-6-oxiranyl-4H-1,3-benzodioxin

A mixture of Intermediate 15 (0.45 g), methanol (10 ml) and anhydrous K₂CO₃ (0.25 g) was stirred at 23° for 2 h. The mixture was diluted with ER(50 ml) filtered through a small wad of silica and evaporated in vacuo.The residual oil was dissolved in ER (50 ml), dried and evaporated togive the title epoxide as an oil (0.27 g). T.l.c. (CX-EA 7:3) Rf 0.56.

Intermediate 17 [4-(2-Propynyloxy)butyl]benzene

A mixture of propargyl alcohol (10.0 g), (4-bromobutyl)benzene (38.0 g),aqueous NaOH (80 ml, 50% w/v), and tetrabutylammonium bisulphate (1.0 g)was stirred vigorously for 3 days, treated with H₂ O (100 ml) andextracted with ER (2×200 ml). The dried extract was evaporated and theresidue was purified on a column of silica (Merck 9385; 500 ml) [H] togive the title compound as a colourless oil (18.3 g). T.l.c. [A] Rf 0.2.

Intermediate 18 [[4-(6-Chloro-2-hexynyl)oxy]butyl]benzene

Intermediate 17 (15.0 g) was added dropwise to a suspension of lithamidefrom lithium (0.61 g) in liquid ammonia (50 ml) at -33°. The mixture wasstirred for 2 h and bromochloropropane (13.9 g) in ER (10 ml) was addeddropwise. The resulting suspension was stirred at -33° for 3 h andammonia was allowed to evaporate overnight. The residue was treatedcautiously with H₂ O (30 ml) and extracted with ER (3×50 ml). The driedextract was evaporated and the residue was distilled to give the titlecompound as a colourless oil (12.9 g) b.p. 140°-150°/0.3 mmHg. T.l.c.[A] Rf 0.2.

Intermediate 19 [[4-(6-Iodo-2-hexynyl)oxy]butyl]benzene

A mixture of Intermediate 18 (12.0 g) sodium iodide (20.0 g), andbutanone (50 ml) was refluxed for 6 h and stirred at RT for 2 days,filtered and evaporated. The residue was dissolved in ER (50 ml) andwashed with H₂ O (50 ml) and aqueous sodium thiosulphate (50 ml). Thedried organic phase was evaporated to leave the title compound as a paleyellow oil (12.6 g).

Intermediate 20 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)-4-hexynyl]amino]methyl]-1,3-benzenedimethanol

Intermediate 19 (8.66 g) was added dropwise to a solution ofIntermediate 1 (6.7 g) and N,N-diisopropylethylamine (3.9 g) in DMF (250ml) at 70°. The mixture was heated at 70° for 2 h and DMF was removedunder reduced pressure. The residue was treated with aqueous NaHCO₃ (1M;200 ml) and extracted with EA (3×250 ml). The dried extract wasevaporated and the residue was purified on a column of silica (Merck9385; 250 ml) [I] to give a yellow oil. Trituration of the oil with ERgave the title compound as a white solid (4.3 g), m.p. 89°-90°. T.l.c.[M] Rf 0.2.

Intermediate 21 3-[[(6-Bromohexyl)oxyl]propyl]benzene

3-Phenylpropanol (3.00 g) and 1,6-dibromohexane (16.10 g, 10.2 ml) werestirred rapidly at RT with tetra-n-butylammonium hydrogen sulphate (0.5g) and 12.5M aqueous NaOH (16 ml) for 30 h. The mixture was diluted withH₂ O (80 ml), extracted with ER (3×100 ml), and the combined organicextracts were washed consecutively with H₂ O (80 ml) and BR (80 ml). Thedried extracts were evaporated and the residual oil purified by [FCS],eluting with CX (one columnful), followed by EA-CX (1:20) to give thetitle compound (5.35 g) as a colourless oil.

Analysis Found:C,60.25;H,7.8;Br,26.45.

C₁₅ H₂₃ BrO requires C,60.2;H,7.75;Br,26.7%.

Intermediate 22 N-[6-(3-Phenylpropoxy)hexyl]benzenemethanaminehydrobromide

Intermediate 21 (317 g) was added to benzylamine (1116 ml) at atemperature of 115°-125° with stirring under nitrogen. Excessbenzylamine was removed by distillation under reduced pressure. Theresidue was treated with methyl isobutyl ketone (1280 ml), thetemperature adjusted to 50° and 47% w/v hydrobromic acid (115 ml) in H₂O (800 ml) was added at 50°-55°. The aqueous phase was removed and theorganic solution was washed with H₂ O (3×800 ml) at 50°. Distillationunder reduced pressure and crystallisation of the residue frompropan-2-ol afforded the title compound salt (318 g), m.p. 135°-136°.

Intermediate 23 Methyl2-hydroxy-5-[[(phenylmethyl)[6-(3-phenylpropoxy)hexyl]amino]acetyl]benzoate

A solution of N,N-diisopropylethylamine (9.93 g) in CH₂ Cl₂ (15 ml) wasadded to a solution of methyl 5-bromoacetyl-2-hydroxybenzoate (10 g) andIntermediate 22 (14.87 g) in CH₂ Cl₂ (256 ml) at 16°. The solution wasstirred under nitrogen for 23 h at 20°, washed with H₂ O (5×100 ml),dried and filtered. This solution of the title compound was used withoutfurther purification. T.l.c. (ER) Rf 0.7.

Intermediate 24 1-[4-[(6-Bromohexyl)oxy]butyl]-2-methoxybenzene

NaH (46% dispersion in oil; 1.36 g) was added portionwise to a solutionof 2-methoxybenzenebutanol (5.0 g) and 1,6-dibromohexane (13.8 g) in THF(50 ml). The suspension was refluxed for 20 h and was treated cautiouslywith H₂ O (20 ml). The resulting emulsion was extracted with ER (2×50ml) and the dried extract was evaporated to leave a yellow oil. The oilwas purified on a column of silica (Merck 9385, 600 ml) [A] to give thetitle compound as a colourless oil (5.6 g). T.l.c. [B] Rf 0.2.

Intermediate 25 Benzenehexanol

(3-Bromopropyl)benzene (20 g) in THF (75 ml) was added dropwise tomagnesium (2.43 g) at a rate to maintain gentle reflux. The mixture wasstirred for 2 h at RT and oxetane (10 g) was added dropwise. Theresulting suspension was stirred at RT for 2 h and at reflux for 16 hand poured into saturated aqueous NH₄ Cl (100 ml). The mixture wasextracted with ER (3×75 ml) and the dried extract was evaporated toleave a yellow oil. Distillation of the oil gave the title compound as acolourless liquid (6.05 g) b.p. 100°-105°/0.4 mmHg. T.l.c. [O] Rf 0.3.

Intermediate 26 2-[(4-Chlorobutyl)oxy]tetrahydropyran

Dihydropyran (15.5 g) was added dropwise to a mixture of 4-chlorobutanol(20 g) and hydrochloric acid (18M, 1 drop) at RT. The mixture wasstirred for 30 min and washed with H₂ O (100 ml), aqueous NaHCO₃ (1M,50ml) and BR (50 ml). The dried liquid was heated under reduced pressureto leave the title compound as a colourless liquid (31.9 g). T.l.c. [L]Rf 0.5.

Intermediate 27 2-[[4-[(6-Phenylhexyl)oxy]butyl]oxy]tetrahydropyran

NaH (3.85 g) was added portionwise to a mixture of Intermediate 25 (5.5g), Intermediate 26 (30 g), potassium iodide (1 g) and THF (50 ml). Themixture was refluxed for 28 h and treated cautiously with H₂ O (100 ml).The resulting emulsion was extracted with ER (3×100 ml) and the driedextract was evaporated to leave a yellow oil. Excess of Intermediate 26was distilled from the mixture at 80°/0.4 mmHg and the residue waspurified on a column of silica (300 ml) [B] to give the title compoundas a colourless oil (2.7 g). T.l.c. [B] Rf 0.25.

Intermediate 28 4-[(6-Phenylhexyl)oxy]butan-1-ol

A solution of Intermediate 27 (2.65 g) in methanol (20 ml) and 80%acetic acid (10 ml) was stirred at RT for 20 h. The solution wasbasified with aqueous NaOH (2M). The mixture was refluxed for 2 h andmethanol was evaporated. The resulting emulsion was extracted with ER(2×50 ml) and the dried extract was evaporated to leave the titlecompound as a colourless oil (2.0 g). T.l.c. [O] Rf 0.3.

Intermediate 29 4-[(6-Phenyhexyl)oxy]butan-1-ol methanesulphonate

Methanesulphonyl chloride (0.4 g) was added dropwise to a solution ofIntermediate 28 (0.8 g) and triethylamine (0.5 g) in CH₂ Cl₂ (5 ml) at0°. The mixture was stirred at RT for 25 min and filtered. The filtratewas washed with saturated aqueous NaHCO₃ (20 ml) and BR (20 ml). Thedried (Na₂ SO₄) organic phase was evaporated to leave the title compoundas a yellow oil (1.0 g).

Intermediate 30 2-[2-[(6-Bromohexyl)oxy]ethyl]-1,3-dimethylbenzene

NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solutionof 2,6-dimethylbenzenethanol (6.0 g) and 1,6-dibromohexane (19.52 g) inTHF (50 ml) under nitrogen. The mixture was refluxed for 18 h andtreated cautiously with H₂ O (20 ml). The resulting emulsion wasextracted with ER (3×100 ml) and the dried extract was evaporated toleave a yellow oil. Excess 1,6-dibromohexane was removed under reducedpressure and the residue was purified on a column of silica (300 ml) [B]to give the title compound as a colourless oil (6.6 g) b.p.110°-115°/0.4 mmHg.

The following intermediates were prepared in a similar manner toIntermediate 21.

Intermediate 31

4-[[(6-Bromohexyl)oxy]butyl]-1-methoxybenzene (3.3 g), b.p.180°-190°/0.5 torr, from 1,6-dibromohexane (8 g) and4-(4-methoxyphenyl)butanol (2 g).

Intermediate 32 5-[[(5-Bromopentyl)oxy]pentyl]benzene (3.2 g), b.p.185°-195°/0.3 torr, from 1,5-dibromopentane (8.5 g) and benzenepentanol(2 g). Intermediate 33

1-[2-[(6-Bromohexyl)oxy]ethyl-4-chlorobenzene (4.0 g), b.p. 169°/0.8torr, from 1,6-dibromohexane (8.65 g) and 4-chlorobenzeneethanol (3.0g).

Intermediate 34

1-[3-[(6-Bromohexyl)oxy]propyl]-4-fluorobenzene (2.22 g), b.p. 170°/0.7torr, from 1,6-dibromohexane (8.82 g) and Intermediate 42 (2.0 g).

Intermediate 35

[2-[(8-Bromooctyl)oxy]ethyl]benzene (4.3 g), T.l.c. [B] Rf 0.3, from1,8-dibromooctane (13.4 g) and benzeneethanol (20 g).

Intermediate 36

[5-[6-(Bromohexyl)oxy]pentyl]benzene (2.7 g), T.l.c. [B] Rf 0.3, from1,6-dibromohexane (9.0 g) and benzenepentanol (2.0 g).

Intermediate 37

1-[2-[(6-Bromohexyl)oxy]ethyl]-4-ethylbenzene (2.6 g), T.l.c. [B] Rf0.25, from 1,6-dibromohexane (9.8 g) and 4-ethylbenzeneethanol (2.0 g).

Intermediate 38

[3-[(7-Bromoheptyl)oxy]propyl]benzene (2.05 g) from 1,7-dibromoheptane(3.83 g) and 3-phenylpropanol (1.08 ml).

Analysis Found: C,62.6; H,8.4. C₁₆ H₂₅ BrO requires C,61.35; H,8.05%.

Intermediate 39

5-[4-[(6-Bromohexyl)oxy]butyl]-1,3-benzodioxolane (3.2 g), T.l.c. (CX-EA4:1) Rf 0.43, from 1,6-dibromohexane (9.5 g) and Intermediate 44 (2.5g).

Intermediate 40

1-[2-[(6-Bromohexyl)oxy]ethyl]-3-chlorobenzene (4.12 g), T.l.c. (ER-HX1:79) Rf 0.16, from 1,6-dibromohexane (11.71 g) and3-chlorobenzeneethanol (2.5 g).

Intermediate 41

1-[3-[(6-Bromohexyl)oxy]propyl]-2-fluorobenzene (4.71 g), T.l.c. (ER-CX1:79) Rf 0.22, from 1,6-dibromohexane (14.28 g) and3-(2-fluorophenyl)-1-propanol (3.0 g).

Intermediate 42 4-Fluorobenzenepropanol

A Grignard reagent was prepared from 4-bromo-1-fluorobenzene (8.0 g),magnesium turnings (1.10 g), and iodine (one small crystal) in THF (40ml). Oxetane (2.3 g) in THF (10 ml) was added at RT and the reactionmixture was heated at reflux overnight. The cooled solution was pouredinto aqueous saturated NH₄ Cl (100 ml), extracted with ER (2×150 ml) andthe combined, dried (Na₂ SO₄) extracts were evaporated. The residual oilwas purified by flash chromatography over silica gel (Merck 9285, 5.0 cmwide column), eluting with ER-CX (1:5→1:3). The resultant oil wasfurther purified by distillation to give the title compound (3.15 g) asa colourless oil, b.p. 150°/0.8 torr.

Intermediate 43 (E/Z)-4-[1,3-Benzodioxol-5-yl]-3-butenol, (E:Z=3:2)

A solution of n-butyllithium in HX (1.6M, 6.5 ml) was added over 5 minto a stirred suspension of[3-(1-methoxy-1-methylethoxy)propyl]triphenylphosphonium bromide (4.8 g)in dry THF (25 ml) at 0° under nitrogen. The mixture was stirred at 0°for 45 min, treated with a solution of piperonal (1.2 g) in dry THF (5ml) and stirred at 0° to 23° over 1 h. ER (70 ml) was added, the mixturefiltered through silica and the filtrate evaporated in vacuo to give ayellow oil which was dissolved in a mixture of THF-H₂ O-2M hydrochloricacid 25:5:1 (31 ml) and kept at 23° for 0.5 h. The mixture was dilutedwith 8% NaHCO₃ (30 ml), extracted with ER (2×50 ml) and the extract waswashed with BR (50 ml), dried and evaporated in vacuo to afford thetitle alcohol as a yellow oil (1.05 g) (E:Z ratio of 3:2). T.l.c. [O] Rf0.22.

Intermediate 44 1,3-Benzodioxole-5-butanol

A solution of Intermediate 43 (3.5 g) in absolute ethanol (50 ml) washydrogenated at RT and atmospheric pressure over 10% palladium on carboncatalyst (200 mg). Hydrogen absorption (392 ml) ceased after 45 min, thesolution was filtered and the filtrate evaporated in vacuo to give thetitle alcohol as a colourless oil (3.5 g). T.l.c. (EA-CX (3:2) Rf 0.49.

The following intermediates were prepared in a similar manner toIntermediate 21.

Intermediate 45

[4-(4-Bromobutoxy)butyl]benzene (2.44 g), T.l.c. [K] Rf 0.68, from1,4-dibromobutane (8.6 g) and benzenebutanol (2 g).

Intermediate 46

[5-(4-Bromobutoxy)pentyl]benzene (2.46 g), T.l.c. [K] Rf 0.58 from1,4-dibromobutane (7.89 g) and benzenepentanol (2 g).

Intermediate 47

[2-[(7-Bromoheptyl)oxy]ethyl]benzene (6.2 g), T.l.c. (CX-ER 40:1) Rf0.29, from 1,7-dibromoheptane (10.5 g) and benzeneethanol (50. g).

Intermediate 48

1-[2-[(5-Bromopentyl)oxy]ethyl]-4-ethylbenzene (2.19 g) T.l.c. [K] Rf0.48, from 1,5-dibromopentane (7.8 g) and 4-ethylbenzeneethanol (1.7 g).

Intermediate 49

1-[2-[(6-Bromohexyl)oxy]ethyl]-4-methylbenzene (8.51 g) T.l.c. [K] Rf0.56 from 1,6-dibromohexane (24.2 g) and 4-methylbenzeethanol (4.5 g).

Intermediate 50

[2-(4-Bromobutoxy)ethyl]benzene (2.85 g), T.l.c. [K] Rf 0.41, from1,4-dibromobutane (10.6 g) and benzeneethanol (2 g).

Intermediate 51

[2-[(5-Bromopentyl)oxy]ethyl]benzene (3.8 g), T.l.c. [K] Rf 0.46 from1,5-dibromopentane (11.3 g) and benzeneethanol (2 g).

Intermediate 52

[3-[(5-Bromopentyl)oxy]propyl]benzene (2.8 g), T.l.c. [K] Rf 0.44 from1,5-dibromopentane (10.2 g) and benzenepropanol (2 g).

Intermediate 53 [4-[(5-Bromopentyl)oxy]butyl]benzene

4-Phenylbutanol (5.80 g) was stirred in 1,5-dibromopentane (52 ml) and5N NaOH solution (50 ml), and tetrabutyl ammonium bisulphate (0.87 g)was added and the reaction mixture was stirred at RT for 72 h. (After 42h the NaOH layer was replaced by a fresh solution). The two layers wereseparated and the aqueous phase was extracted with ER (3×50 ml). Thecombined organic layers were dried (Na₂ SO₄), and evaporated to give aclear liquid. Excess 1,5-dibromopentane was removed by distillation at60° 1.00 mmHg. The residue was chromatographed on a silica (70-230 mesh,30 g) column using CX as eluant, with a slowly increasing quantity of ERuntil the title compound was obtained, which on evaporation gave acolourless oil (3.26 g). T.l.c. (CX-ER (99:1)) Rf 0.15.

Intermediate 54 1-[2-[(6-Bromohexyl)oxy]ethyl]-4-methoxybenzene

4-Methoxybenzeneethanol (5.0 g) and 1,6-dibromohexane (23.7 g) werestirred rapidly at RT with tetra-n-butyl ammonium bisulphate (0.94 g)and 12.5M aqueous NaOH (30 ml) for 16 h. The mixture was diluted with H₂O (125 ml), extracted with ER (3×150 ml) and the combined organicextracts were washed consecutively with H₂ O (125 ml), BR (125 ml),dried and evaporated to give an oil (24.6 g). The oil was purified by[FCS] eluting with ER-CX (0:100→4:96) to give the title compound as acolourless oil (8.30 g). T.l.c. (CX-ER (40:1)) Rf 0.33.

Intermediate 55 7-[2-(Phenylethoxy)]-2-heptanone

A solution of Intermediate 51 (2.0 g) in ER (15 ml) was added dropwiseto magnesium (0.18 g). The mixture was refluxed for 1 h, cooled andadded during 40 min to acetic anhydride (1.4 g) in ER (10 ml) at -78°.The suspension was stirred at -78° for 2 h, warmed to -10° and treatedwith saturated aqueous NH₄ Cl (20 ml). The mixture was extracted with ER(2×25 ml) and the extract was washed with 5% NaOH (20 ml) and BR (20ml). The dried extract was evaporated and the residue was purified on acolumn of silica (100 ml) [L] to give the title compound as a colourlessoil (0.70 g). T.l.c. [L] Rf 0.25.

The following ketones were prepared in a similar manner: (Intermediates57, 62 and 64 are described after Intermediate 65)

Intermediate 56

7-[4-(Phenylbutoxy)]-2-heptanone (1.15 g) from Intermediate 53 (3.0 g)and acetic anhydride (2 g). T.l.c. [L] Rf 0.25.

Intermediate 58

6-(3-Phenylpropoxy)-2-hexanone (1.3 g) from Intermediate 57 (3.5 g) andacetic anhydride (2.6 g). T.l.c. [L] Rf 0.25.

Intermediate 59

6-(4-Phenylbutoxy)-2-hexanone (1.3 g) from Intermediate 45 (3.0 g) andacetic anhydride (2.3 g). T.l.c. [L] Rf 0.35.

Intermediate 60

8-(2-Phenylethoxy)-3-octanone (4.35 g) from Intermediate 51 (7.0 g) andpropionic anhydride (6.53 g). T.l.c. (CX-ER 7:1) Rf 0.22.

Intermediate 61

9-(2-Phenylethoxy)-4-nonanone (2.25 g) from Intermediate 51 (5.0 g) andbutyric anhydride (6.75 g). T.l.c. [B] Rf 0.2.

Intermediate 63

7-[2-(4-Fluorophenyl)ethoxy]-2-heptanone (1.88 g) from Intermediate 62(6.0 g) and acetic anhydride (4.2 g), b.p. 172°/0.7 Torr.

Intermediate 65

7-[3-(4-Methoxyphenyl)propoxy]-2-heptanone (2.17 g) from Intermediate 64(5.5 g) and acetic anhydride (3.66 g). T.l.c. [F] Rf 0.18.

Intermediate 57 [[3-(4-Bromobutoxy)]propyl]benzene

A mixture of 3-phenylpropanol (2 g), tetrabutylammonium bisulphate (0.5g) 1,4-dibromobutane (9.5 g) and 50% NaOH (11 ml) was stirred at RT for22 h, diluted with H₂ O (250 ml) and extracted with ER (250 ml). Theorganic phase was washed successively with H₂ O (250 ml) and BR (250ml), dried and evaporated under reduced pressure to give a colourlessoil. Purification by [FCS] [120 g], eluting with CX followed by [K]afforded the title compound as a colourless oil (2.72 g). T.l.c. (CX-EA1:9) Rf 0.51.

Intermediate 62 1-[2-[(5-Bromopentyl)oxy]ethyl]-4-fluorobenzene

4-Fluorobenzeneethanol (10.0 g), 1,5-dibromopentane (29 ml),tetra-n-butylammonium hydrogen sulphate (3.2 g, 9 mmol), and aqueous12.5M NaOH (109 ml) were stirred vigorously at RT overnight. The mixturewas diluted with H₂ O (400 ml), extracted with ER (3×200 ml), and thecombined organic extracts were evaporated. The residual oil was purifiedby [FCS] eluting with CX-ER (100:0→100:6), to give the title compound asa colourless oil (14.37 g). T.l.c. (ER-CX, 19:1) Rf 0.22.

Intermediate 64 1-[3-[(5-Bromopentyl)oxy]propyl]-4-methoxybenzene

4-Methoxybenzenepropanol (7.5 g) and 1,5 dibromopentane (30.5 g) werestirred rapidly at RT with tetra-n-butylammonium bisulphate (1.02 g) and12.5M aqueous NaOH (36 ml) for 16 h. The mixture was diluted with H₂ O(170 ml), extracted with ER (3×200 ml) and the combined organic extractswere washed consecutively with H₂ O (170 ml) and BR (170 ml), dried andevaporated to give an oil (34.8 g). The oil was purified by [FCS]eluting with ER-CX (0:100→4:96) to give the title compound as acolourless oil (8.83 g). T.l.c. (CX-ER 79:1) Rf 0.1.

Intermediate 66 1,1-Dimethyl-5-(3-phenylpropoxy)-2-pentynamine

1,1-Dimethylpropargylamine (8.5 g) was added dropwise to a suspension oflithamide [from lithium (1.7 g)] in liquid ammonia (100 ml) at -33°. Themixture was stirred for 90 min and a solution of[3-(2-bromoethoxy)propyl]benzene (21.5 g) in ER (30 ml) was addeddropwise. The suspension was stirred for 4 h and ammonia was allowed toevaporate overnight. The residue was treated with H₂ O (100 ml) andextracted with ER (3×100 ml). The dried extract was evaporated and theresidue was distilled to give the title compound as a colourless oil(3.0 g) b.p. 160°-165°/0.2 mmHg. T.l.c. (ER) Rf 0.3.

Intermediate 67 α¹-[[[1,1-Dimethyl-5-(3-phenylpropoxy)-2,E-pentenyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

A solution of methyl 5-(bromoacetyl)-2-hydroxybenzoate (3.3 g)Intermediate 66 (2.9 g) and N,N-diisopropylethylamine (1.55 g) in EA (50ml) was refluxed for 3 h, filtered and evaporated. The residue wasdissolved in ER (50 ml), filtered, and added dropwise to a suspension ofLiAlH₄ (2 g) in ER (100 ml) at 0° under nitrogen. The mixture wasstirred at 0° for 1 h at RT for 1 h and was treated cautiously with H₂ O(10 ml). The mixture was acidified to pH 1 with hydrochloric acid (2M),and basified with solid KHCO₃ to pH8. The ER layer was decanted off andthe aqueous slurry was extracted with CHCl₃ (3×500 ml). The driedextract was evaporated to leave an orange oil. The oil was purified on acolumn of silica (300 ml) eluted with EA-methanol-triethylamine (93:7:1)to give the title compound as a white solid (0.88 g) m.p. 108°-109°.T.l.c. [M] Rf 0.25.

Intermediate 68 1,1-Dimethyl-7-(2-phenylethoxy)heptanoic acid

n-Butyllithium in HX (1.6M; 172 ml) was added dropwise todiisopropylamine (27.5 g) in THF (40 ml) at -78° under nitrogen. Themixture was warmed to 0°, stirred for 45 min, and isobutyric acid (12.0g) was added dropwise. The resulting suspension was stirred at RT for 4h and Intermediate 51 (25.0 g ) was added dropwise. The mixture wasstirred for 16 h at RT, treated slowly with hydrochloric acid (2M; 350ml), and extracted with ER (2×250 ml). The dried extract was evaporatedand the residue was purified on a column of silica (Merck 9385; 300 ml)[B] to give the title compound as a colourless oil (17.0 g). T.l.c. [L]Rf 0.35.

Intermediate 69 1-1-Dimethyl-6-(2-phenylethoxy)hexylcarbamic acid,phenylmethyl ester

Ethyl chloroformate (3.26 g) in acetone (10 ml) was added to a solutionof Intermediate 68 (8.0 g) and triethylamine (3.03 g) in acetone (100ml) and H₂ O (10 ml) at 0°. The mixture was stirred for 40 min at 0° andsodium azide (2.25 g) in H₂ O (25 ml) was added dropwise. The resultingsuspension was stirred at RT for 30 min, diluted with H₂ O (200 ml), andextracted with toluene (2×200 ml). The dried (Na₂ SO₄) extract wasevaporated to half-volume, heated at 70°-80° for 2 h, and toluene wasremoved under reduced pressure. The resulting isocyanate in benzylalcohol (20 ml) was heated at 80°-83° for 60 h and benzyl alcohol wasremoved under reduced pressure (1 Torr). The residue was purified in acolumn of silica (Merck 9385; 300 ml) eluted with CX-ER (17:3) to givethe title compound as a colourless oil (7.45 g). T.l.c. [L] Rf 0.25.

Intermediate 70 1,1-Dimethyl-6-(2-phenylethoxy)hexanamine

A solution of Intermediate 69 (6.8 g) in ethanol (100 ml) washydrogenated over 10% palladium on charcoal (0.5 g) for 40 min filtered,and evaporated to give the title compound as a colourless oil (4.3 g).

Intermediate 71 Methyl5-[2-(dimethylamino)-1-hydroxyethyl]-2-(phenylmethoxy)benzoate

Dimethylamine (33% in ethanol, 156 ml) was added to a stirred suspensionof methyl 5-(bromoacetyl)-2-(phenylmethoxy)benzoate (105.8 g) inabsolute ethanol (1 l) and THF (1 l). The resulting solution was stirredat RT for 2 h, treated with NaBH₄ (25 g) and stirred at RT overnight.The solvent was removed in vacuo and H₂ O (500 ml) was added to theresidue. The mixture was extracted with EA (2×500 ml), the combinedextracts were washed with H₂ O and BR, dried (Na₂ SO₄) and concentratedin vacuo. The product was purified twice by [FCS] eluted withEA-methanol-triethylamine (80:20:1) to give the title compound as a fawnsolid (59.8 g) m.p. 79°-81°.

Intermediate 72 (R)-Methyl5-[2-(dimethylamino)-1-hydroxyethyl]-2-(phenylmethoxy)benzoate[S-(R*,R*)-2,3-bis[(4-methylbenzoyl)oxy]butanedioate (1:1) (salt)

Intermediate 71 (50 g) in hot methanol (250 ml) was mixed with(-)-di-p-toluoyl tartaric acid, monohydrate (60 g) in hot methanol (250ml). The resulting precipitate was collected by filtration andrecrystallised three times from methanol (25 ml/gram) to give the titlecompound as white needles (16.4 g). m.p. 169°-170° [α]_(D) ¹⁸.2° -103.3°(c 0.51 in CH₃ OH)

Intermediate 73 (R)-Methyl5-[2-(dimethylamino)-1-hydroxyethyl]-2-(phenylmethoxy)benzoate

Intermediate 72 (16.4 g) was partitioned between EA (175 ml) and 6Nammonium hydroxide (8.4 ml) in H₂ O (175 ml). The organic layer waswashed with 8% NaHCO₃ (2×100 ml), BR, dried (Na₂ SO₄) and concentratedin vacuo to give the title compound as a viscous oil (7.9 g) T.l.c.(EA-methanol-triethylamine 80:20:1) Rf=0.23.

Intermediate 74(R)-β-Hydroxy-3-(methoxycarbonyl)-N,N,N-trimethyl-4-(phenylmethoxy)benzeneethanaminium iodide

Intermediate 73 (7.85 g) and methyl iodide (17.5 ml) in acetone (55 ml)was stirred at reflux under nitrogen for 3 h. The acetone was removed invacuo and CHCl₃ (100 ml) was added to the residue. The resultingprecipitate was collected by filtration and dried in vacuo (12.2 g).Recrystallisation from methanol gave the title compound as an off-whitesolid (4.5 g) m.p. 85°-120° [α]_(D) ²⁰.2 -32.2° (c 0.7 in DMSO)

Intermediate 75 (R)-Methyl 5-oxiranyl-2-(phenylmethoxy)benzoate

A warm suspension of Intermediate 74 in dry acetonitrile (200 ml) wastreated with tetramethylammonium fluoride-bi-methanol solvate (5.5 g)and stirred at reflux, with continuous removal of the distillate, for2.5 h. The cooled reaction mixture was filtered and the filtrate wasconcentrated in vacuo to a semi-solid. Dry ER (100 ml) was added and themixture was refiltered. The filtrate was concentrated to an oil whichwas purified by [FCS] eluting with CX-EA-triethylamine 80:20:1 to givethe title compound as a colourless oil (1.98 g). [α]_(D) ²³.3° +19.9° (c0.86 in benzene)

T.l.c. (CX-EA-triethylamine 80:20:1) Rf=0.14.

Intermediate 76 (R)-Methyl5-[1-hydroxy-2-[(phenylmethyl)[6-(3-phenylpropoxy)hexyl]amino]ethyl]-2-(phenylmethoxy)benzoate

Intermediate 75 (1.9 g) and Intermediate 22, free base (2.17 g) inmethanol (50 ml) were stirred at reflux, under nitrogen, for 6 h. Thesolvent was removed in vacuo and the residual oil was purified by [FCS]eluting with CX-EA-triethylamine 75:25:1 to give the title compound as apale yellow oil (2.1 g). [α]_(D) ²⁰.6° -62.4° (c 0.74 in T.l.c.

(CX-EA-triethylamine 80:20:1) Rf=0.12.

Intermediate 77 (R)-(-)-4-(Phenylmethoxy)-α¹-[[(phenylmethyl)[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

Intermediate 76 (2.0 g) in dry THF (40 ml) was added to a stirredsuspension of LiAlH₄ (300 mg) in dry THF (40 ml) at RT, under nitrogen.The reaction mixture was placed in an oil-bath, preheated to 80°, andstirred at reflux for 5 min. The cooled mixture was treated cautiouslywith H₂ O (40 ml) and ER (40 ml. The phases were separated and theaqueous phase was re-extracted with ER (50 ml). The combined organicphases were washed with H₂ O and BR, dried (Na₂ SO₄) and concentrated invacuo. [FCS] using CX-EA-triethylamine 66:33:1 as eluant gave the titlecompound as a clear, colourless oil (1.70 g). [α]_(D) ²¹° -64.6° (c 0.6in CHCl₃) T.l.c. (CX-EA-triethylamine 66:33:1) Rf=0.15

EXAMPLE 1 4-Hydroxy-α¹-[[[6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, hydrate

A mixture of Intermediate 1 (0.93 g), Intermediate 2 (1.6 g), pyridine(1 ml) and DMF (25 ml) was left at RT for 2 weeks. The resultingsolution was evaporated and the residue was purified on a column ofsilica (Merck 9385: 250 ml) [I] to give a yellow oil. The oil wastriturated with ER to give the title compound as a cream solid (0.20 g)m.p. 89°-91°. T.l.c. [M] Rf 0.1.

EXAMPLE 2 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 1 (8.9 g), potassium iodide (4.0 g),triethylamine (5 ml) and DMF (250 ml) at 70° was treated dropwise withIntermediate 3 (7.5 g). The solution was heated at 65°-70° for 1 h andDMF was removed under reduced pressure. The residue was treated with H₂O (200 ml) and the resulting emulsion was extracted with EA (3×300 ml).The combined extracts were washed with H₂ O (2×50 ml) and BR (50 ml),dried and evaporated. Trituration of the residue with ER/10% EA (200 ml)for 16 h gave a suspension from which the title compound was collectedas a white solid (2.6 g), m.p. 75.5°-76.5°. T.l.c. [M] Rf 0.2.

EXAMPLE 3 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 4 (2.2 g) and Intermediate 6 (1.0 g) inabsolute ethanol (25 ml) was hydrogenated at RT and atmospheric pressureover 10% palladium on carbon catalyst (0.2 g). The mixture was filteredthrough hyflo and evaporated to give an oil. Purification by [FCTS] (40g) [N] gave an oil which on trituration with ER afforded the titlecompound as a white solid (0.77 g) m.p. 75°-76°, mixed m.p. 74°-76° withthe product of Example 2. T.l.c. EN [N] Rf 0.31.

EXAMPLE 4 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl)]amino]methyl]-1,3-benzenedimethanol

Intermediate 6 (0.5 g) was added to a stirred suspension of Intermediate1 (0.5 g) in methanol (5 ml) at 23°. The mixture was stirred for 0.5 h,NaBH₄ (0.5 g) was added and stirring continued for 7 h. The mixture wasdiluted with H₂ O (50 ml), extracted with EA (2×25 ml) and the organicphase was washed with BR (25 ml), dried and evaporated to give an oil.Purification by [FCTS] (30 g) afforded an oil which on trituration withcold ER gave the title compound as a white solid (0.25 g), m.p. 76°-77°,mixed m.p. 75°-76° with the product of Example 2. T.l.c. EN [N] Rf 0.31.

EXAMPLE 5 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 7 (51 g) and4-bromoacetyl-2-(hydroxymethyl)phenol diacetate [prepared from 36.25 gof 4-acetyl-2-(hydroxymethyl)phenol diacetate] in CHCl₃ (410 ml) wasstirred at the reflux for 24 h, cooled and concentrated under reducedpressure. The residual oil was dissolved in toluene (75 ml) andconcentrated. The oil was dissolved in toluene (125 ml), washed with H₂O (150 ml) and BR (50 ml). The aqueous solutions were extracted withtoluene (30 ml) and the combined extracts were washed with H₂ O (50 ml)and concentrated. The crude ketoamine diacetate was stirred in ethanol(155 ml) and 10N hydrochloric acid (48 ml) in H₂ O (58 ml) was addeddropwise with stirring, the temperature being maintained below 20°.After being allowed to stand at 0° for 2 days the solution was treatedwith ethanol (180 ml) and NaOH (17.6 g) in H₂ O (18 ml) whilst keepingthe temperature below 15°. NaBH₄ (11.06 g) and NaOH (2.11 g) in H₂ Owere added, followed after 24 h by more NaBH₄ (9.5 g) over a period of48 h. The mixture was neutralised with 2N sulphuric acid andconcentrated to a slurry which was partitioned between 2N Na₂ CO₃ (100ml) and EA (200 ml). The organic layer was treated with a furtherquantity of 2N Na₂ CO₃ (100 ml) and EA (200 ml). The combined organicextracts were washed, dried and evaporated. The crude triol waschromatographed on Sorbsil (700 g), [G] to give the title compound (26.5g) identified by its n.m.r. spectrum.

EXAMPLE 6 4-Hydroxy-α.sup. 1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 8 (0.4 g) in absolute ethanol (25 ml) washydrogenated at 23° and atmospheric pressure over 10% palladium oncarbon (0.2 g) and 10% platinum on carbon (0.2 g) catalysts. The mixturewas filtered through hyflo and evaporated to give an oil. Purificationby [FCTS] (20 g) [N] afforded an oil which on trituration with ER gavethe title compound as a white solid (0.21 g) m.p. 76.5°-77.5° , mixedm.p. 75.5°-76.5° with the product of Example 2. T.l.c. EN [N] Rf 0.31.

EXAMPLE 72,2-Dimethyl-α[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-4H-1,3-benzodioxin-6-methanol

A solution of Intermediate 10 (1 g) in absolute ethanol (20 ml) washydrogenated at 23° and atmospheric pressure over 10% palladium oncarbon (0.1 g) and 10% platinum on carbon (0.1 g) catalysts. The mixturewas filtered through hyflo and evaporated in vacuo to give an oil whichslowly crystallised. The solid was slurried in HX, filtered off anddried to give the title compound as white crystals (0.72 g) m.p.68°-70°. T.l.c. EN (EA-MeOH 19:1) Rf 0.45.

EXAMPLE 8 4-Hydroxy-α¹[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 12 (0.3 g) in dry THF (5 ml) was added to astirred suspension of LiAlH₄ (0.26 g) in dry THF (15 ml) at 0° undernitrogen. The mixture was stirred at 23° for 20 h, diluted cautiouslywith H₂ O (30 ml), acidified to pH5 with 2M hydrochloric acid, basifiedto pH8 with NaHCO₃ and extracted with EA (3×50 ml). The organic phasewas washed with BR (50 ml), dried (Na₂ SO₄) and evaporated to give anoil which was purified by [FCTS] [N] to give an oil. Trituration withcold ER afforded the title compound as a white solid (0.064 g) m.p.75°-76.5° mixed m.p. 75°-76° with the product of Example 2. T.l.c. EN[N]Rf 0.31.

EXAMPLE 9 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 13 (0.91 g) in THF (10 ml) was added over 15min to a stirred solution of methyl 5-(bromoacetyl)-2-hydroxybenzoate (1g) and N,N-diisopropylethylamine (0.85 g) in THF (10 ml) at 0°. Themixture was stirred at 0° for 2 h, diluted with ether (50 ml), washedwith 0.5M hydrochloric acid (50 ml), 8% NaHCO₃ (50 ml), BR (50 ml),dried and evaporated to give an oil. Purification by [FCS] (60 g) [O]afforded the intermediate glycyl compound as an oil (0.6 g). A solutionof this oil (0.6 g) in dry THF (5 ml) was added to a stirred slurry ofLiAlH₄ (0.25 g) in dry THF (25 ml) under nitrogen at 23°. The mixturewas stirred for 18 h, diluted cautiously with H₂ O (50 ml), acidified topH5 with 2M hydrochloric acid, basified to pH8 with NaHCO₃ and extractedwith EA (2×100 ml). The dried extract was evaporated to give an oilwhich was purified by [FCTS] (20 g) [N] to give an oil which ontrituration with ER afforded the title compound as a white powder (0.12g) m.p 75.5°-76.5°, mixed m.p. 75°-76° with the product of Example 2.T.l.c. EN [N] Rf 0.31.

EXAMPLE 10 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol.

A solution of Intermediate 14 (0.58 g) in dry THF (10 ml) was added over10 min to a stirred suspension of LiAlH₄ (0.5 g) in dry THF (25 ml) at0° under nitrogen. The mixture was stirred at 23° for 18 h, dilutedcautiously with H₂ O (50 ml), acidified to pH5 with 2M hydrochloricacid, basified to pH8 with NaHCO₃ and extracted with EA (3×50 ml). Theextract was washed with BR (50 ml) dried (Na₂ SO₄) and evaporated togive an oil which was purified by [FCTS] [N] to give a pale yellow oil.Trituration with cold ER gave the title compound as a white solid (0.115g) m.p. 76°-77° mixed m.p. 75.5-76.5 with the product of Example 2.T.l.c. EN [N] Rf 0.31.

EXAMPLE 112,2-Dimethyl-α-[[[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]methyl]-4H-1,3-benzodioxin-6-methanol

A solution of Intermediate 16 (0.24 g) and Intermediate 7 (0.8 g) in dryTHF (3 ml) was refluxed under nitrogen for 24 h. The mixture wasevaporated and the residue purified by [FCS] [J] to afford the titlecompound as a pale yellow oil (0.18 g). T.l.c. [O] Rf 0.49.

EXAMPLE 122,2-Dimethyl-α-[[[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]methyl]-4H-1,3-benzodioxin-6-methanol

A solution of Intermediate 15 (0.2 g) and Intermediate 7 (0.7 g) in dryTHF (5 ml) was refluxed under nitrogen for 18 h. The mixture was dilutedwith ER (15 ml), washed with 8% NaHCO₃ solution (15 ml), BR (10 ml),dried and evaporated to give an oil (0.8 g). Purification by [FCS] (20g) [J] afforded the title compound as a pale yellow oil (0.09 g). T.l.c.[O] Rf 0.49.

EXAMPLE 13 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of the product of Example 7 (0.3 g) in methanol (2 ml) wasdiluted with 2M hydrochloric acid (2 ml) and the solution was kept at23° for 5 h. EA (15 ml) was added and the mixture washed with 8% NaHCO₃(15 ml), BR (15 ml), dried and evaporated in vacuo to give a colourlessoil. Trituration with ER afforded the title compound as a white solid(0.23 g) m.p. 76°-77°, mixed m.p. 75.5°-77° with the product of Example2. T.l.c. EN[N] Rf 0.31.

EXAMPLE 14 4-Hydroxy-α¹-[[[6-4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

The product described in Example 5 (230 g) in ethanol (1.3 l) wasreduced by hydrogen in the presence of 10% palladium-on-carbon catalyst(46.5% paste in H₂ O; 60 g). Catalyst and solvent were removed and ER (2l) was added to the residue. The solution was decanted from a littleinsoluble gum and left to stand overnight. Filtration of the mixtureafforded the title compound (147 g), m.p. 75°-77°.

EXAMPLE 15 4-Hydroxy-α¹-[[[6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, hydrate

A solution of Intermediate 20 (30 mg) in EA (20 ml) was hydrogenatedover palladium-charcoal (10%, ˜20 mg) for 5 h, filtered through Hyfloand concentrated under reduced pressure to give the title compound as apal yellow solid (27 mg). T.l.c. (EA-ethanol-NH₃ 10:1:1) Rf 0.3.H.p.l.c. Column: 5 μ Hypersil 5 mm×10 mm; λ max: 276 nm; Flowrate: 2ml/min; Eluant: HX-EA-Isopropanol-NH₃ 10:1:1:0.15 Retention time 11.5min.

EXAMPLE 16 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol benzoatesalt

A solution of the compound of Example 2 (2.3 g) in EA (5 ml) at 40° wasadded to a solution of benzoic acid (0.7 g) in EA (5 ml) at 40°. Thesolution was cooled to 0° and EA was decanted from the resulting solid.The solid was washed with ER (3×5 ml) and recrystallised from EA to givethe title compound as a white solid m.p. 117°-117.5°.

EXAMPLE 17 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol2-hydroxybenzoate (salt)

A solution of 2-hydroxybenzoic acid (0.83 g) in warm isopropanol (10 ml)was added to the compound of Example 2 (2.50 g) in isopropanol (10 ml).The mixture was aged overnight at ambient temperature then the productwas collected, washed with isopropanol (3×5 ml) and dried in vacuo at60°, to give the title salt as a colourless solid, m.p. 134°-135°

The following salts (Examples 18-21) were prepared in a similar mannerfrom the compound of Example 2.

EXAMPLE 18 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol4-chlorobenzoate (salt)

The product melted at 117°-119°, partially resolidified and remelted at134°.

EXAMPLE 19

4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol4-hydroxybenzoate (salt), m.p. 136.5°-138°.

EXAMPLE 20

4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol1-hydroxy-2-naphthalenecarboxylate (salt), m.p. 137°-138°.

EXAMPLE 21

4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol3-hydroxy-2-naphthalenecarboxylate (salt), m.p. 135°-137°.

EXAMPLE 22 4-Hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol sulphate(2:1) (salt)

Sulphuric acid (98% w/w, 613 mg) was added to ethanol (10 ml) and aportion of the solution (5.2 ml) was added to a warm solution of thebase of the compound of Example 2 (2.5 g) in ethanol (10 ml). On beingallowed to stand in an open necked flask for 24 h the solution depositedwhite needles which were filtered off, washed with ethanol (2×5 ml) anddried at 50° in vacuo to give the title salt (1.89 g), m.p.117.5°-119.5°.

EXAMPLE 23 4-Hydroxy-α¹-[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A mixture of Intermediate 1 (0.84 g), Intermediate 21 (1.0 g),N,N-diisopropylethylamine (0.706 g, 0.95 ml) and DMF (7.3 ml) was heatedat 80° for 1 h. The clear brown solution was diluted with H₂ O (75 ml),acidified to pH4 with 2N hydrochloric acid and then basified to pH8 withsolid KHCO₃. The cloudy aqueous phase was extracted with EA (2×75 ml)and the combined extracts were washed successively with H₂ O (75 ml) andBR (35 ml). The combined dried (Na₂ SO₄) extracts were evaporated andthe residual oil was purified by [FCS] [I] to give, after triturationwith ER (25 ml) the title compound (0.279 g) as a white solid m.p.77°-78°. T.l.c. [I] Rf 0.13.

EXAMPLE 24 4-Hydroxy-α¹-[[(phenylmethyl)-[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

Intermediate 23 was added during 15 min to a solution of sodiumbis(2-methoxyethoxy)aluminium hydride (3.4M solution in toluene; 33 ml)and CH₂ Cl₂ (50 ml), whilst maintaining the temperature between 4° and18°, under nitrogen. After 1.75 h at 15° the mixture was cooled to 5°and treated very cautiously with H₂ O (10 ml). The filtrate wasevaporated under reduced pressure and the residue in EA (250 ml) wastreated with 2N hydrochloric acid (250 ml). The organic layer was washedsuccessively with 2N Na₂ CO₃ solution (200 ml) and H₂ O (200 ml), driedand evaporated to give the title compound as an orange oil (15.8 g).T.l.c. (ER) Rf 0.3.

EXAMPLE 25 4-Hydroxy-α¹-[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

The product of Example 24 (19 g) in ethanol (150 ml) was hydrogenated inthe presence of 10% palladium-on-charcoal catalyst (5.2 g). After 2 h 40min the mixture was filtered and the filtrate evaporated under reducedpressure to a pale yellow oil, which crystallised from EA to give thetitle compound as a white solid, (10.1 g) m.p. 82°-84°.

Analysis Found: C,71.76;H,8.60;N,3.43. C₂₅ H₃₅ NO₄ requiresC,71.78;H,8.79;N,3.49%.

EXAMPLE 26 4-Hydroxy-α¹-[[(phenylmethyl)-[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of 4-bromoacetyl-2-(hydroxymethyl)phenol diacetate [preparedfrom 4-acetyl-2-(hydroxymethyl)phenol diacetate (30 g)] in CHCl₃ (221ml) was treated with propylene oxide (16.7 g) and Intermediate 22hydrochloride (43.4 g). The mixture was stirred and heated at reflux for24 h, and allowed to cool to RT. Solvent was removed under reducedpressure, the residue was dissolved in toluene (200 ml) and washed withH₂ O (2×50 ml). The toluene solution was evaporated to dryness and theresidue was dissolved in a mixture of ethanol (270 ml), H₂ O (117 ml),and 10N hydrochloric acid (89 ml). The mixture was allowed to stand atRT for 48 h and evaporated to dryness to give an oil. This crudehydrochloride was dissolved in ethanol (283 ml) and the stirred solutionwas treated with a solution of NaOH (3.53 g) in H₂ O (3.53 ml) keepingthe temperature below 20°. The solution was cooled to below 10°, and asolution of NaBH₄ (9.15 g) and NaOH (1.26 g) in H₂ O (34.9 ml) was addedover 0.5 h keeping the temperature below 10°. The mixture was stirred at20° for 24 h and then adjusted to pH 7.3 with 5N sulphuric acid andevaporated to dryness. The residue was dissolved in a mixture of EA (291ml) and 2N Na₂ CO₃ (176 ml). The aqueous phase was extracted with EA(2×117 ml), the combined EA solution was washed with 1N Na₂ CO₃ (162 ml)and H₂ O (8×162 ml) and then evaporated to dryness. The resulting oilwas purified by column chromatography (Sorbsil, 500 g) [O] to give thetitle compound as an oil (17.0 g). This compound was reduced, asdescribed in Example 25, to the compound of Example 23.

EXAMPLE 27 4-Hydroxy-α¹-[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol,sulphate (2:1) salt

A solution of concentrated sulphuric acid (0.3 g) in ethanol (5 ml) wasadded to a warm solution of the base of Example 23 (2.4 g) in ethanol(10 ml). The title salt precipitated as a white solid (1.9 g), m.p.111°-112°.

EXAMPLE 28 4-Hydroxy-α¹-[[[6-[4-(2-methoxyphenyl)butoxy]hexyl]amino]methyl]-1,3-benzenedimethanol

Intermediate 24 (2.0 g) was added dropwise to a solution of Intermediate1 (2.13 g), triethylamine (5 ml), and potassium iodide (0.95 g) in DMF(50 ml) at 70°. The solution was heated at 70°-75° for 1 h and added toH₂ O (800 ml). The resulting emulsion was extracted with EA (3×200 ml)and the dried extract was evaporated to leave an orange oil. The oil waspurified on a column of silica (150 ml) [I] to leave a colourless oil.The oil was crystallised from EA to give the title compound as anoff-white solid (0.80 g) m.p. 52°-54°. T.l.c. [M] Rf 0.2.

EXAMPLE 29 4-Hydroxy-α¹-[[[4-[(6-phenylhexyl)oxy]butyl]amino]methyl]-1,3-benzenedimethanol

Intermediate 29 (1.0 g) was added dropwise to a solution of Intermediate1 (1.2 g) and triethylamine (2 ml) in DMF (30 ml) at 60°. The solutionwas stirred at 60°-70° for 4 h and added to H₂ O (500 ml). The resultingemulsion was extracted with EA (3×150 ml) and the dried extract wasevaporated to leave a brown oil. The oil was purified on a column ofsilica (Merck 9385; 150 ml) [I] to leave a yellow gum. The gum wasrepurified on a column of silica (Merck 9385, 50 ml) eluted withEA-methanol (93:7) to leave a colourless oil. Trituration of the oilwith ER (10 ml) gave the title compound as a white solid (0.07 g) m.p.75°-77°. T.l.c. [M] Rf 0.15

EXAMPLE 30 α¹-[[[6-[2-(2,6-Dimethylphenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol, hemihydrate

Intermediate 30 (2.0 g) was added dropwise to a solution of Intermediate1 (2.34 g), potassium iodide (0.9 g) and triethylamine (4 g) in DMF (60ml) at 60°. The solution was stirred at 60°-70° for 1 h and added to H₂O (800 ml). The emulsion was evaporated to leave a yellow oil.Purification of the oil on a column of silica (100 ml) [I] gave acolourless oil. Trituration of this oil with ER (25 ml) gave a whitesolid which was crystallised from EA to give the title compound as awhite solid (0.43 g) m.p. 83°-86°. T.l.c. [M] Rf 0.15

The following Examples were prepared in a similar manner to thatdescribed for Example 23 from Intermediate 1 and the other Intermediateshown in the Table.

Example 31: 4-Hydroxy-α¹-[[[6-[4-(4-methoxyphenyl)butoxy]hexyl]amino]methyl]-1,3-benzenedimethanol

Example 32: 4-Hydroxy-α¹-[[[5-[(5-phenylpentyl)oxy]pentyl]amino]methyl]1,3-benzenedimethanol

Example 33: α¹-[[[6-[2-(4-Chlorophenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Example 34: α¹-[[[6-[3-(4-Fluorophenyl)propoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Example 35: 4-Hydroxy-α¹-[[8-[(2-phenylethoxy)octyl]amino]methyl]-1,3-benzenedimethanol

Example 36: 4-Hydroxy-α¹-[[[6-[(5-phenylpentyl)oxy]hexyl]amino]methyl]-1,3-benzenedimethanol

Example 37: α¹-[[[6-[2-(4-Ethylphenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Example 38: 4-Hydroxy-α¹-[[[7-(3-phenylpropoxy)heptyl]amino]methyl]-1,3-benzenedimethanol

Example 39: α¹-[[[6-[4-(1,3-Benzodioxol-5-yl)butoxy]hexyl]amino]methyl-4-hydroxy-1,3-benzenedimethanol

Example 40: α¹-[[[6-[2-(3-Chlorophenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Example 41: 4-Hydroxy-α¹-[[[6-(phenylmethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

Example 42: α¹-[[[6-[3-(2-Fluorophenyl)propoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Example 43: 4-Hydroxy-α¹-[[[(4-phenylbutoxy)butyl]amino]methyl]-1,3-benzenedimethanol

Example 44: 4-Hydroxy-α¹-[[[[4-(5-phenylpentyl)oxy]butyl]amino]methyl]1,3-benzenedimethanol

Example 45: 4-Hydroxy-α¹-[[7-[(2-phenylethoxy)heptyl]amino]methyl]-1,3-benzenedimethanol

Example 46: α¹-[[[5-[2-(4-Ethylphenyl)ethoxy]pentyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Example 47: 4-Hydroxy-α¹-[[[6-[2-(4-methylphenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol

Example 48: 4-Hydroxy-α¹-[[[4-(2-phenylethoxy)butyl]amino]methyl]-1,3-benzenedimethanol

Example 49: 4-Hydroxy-α¹-[[[5-(2-phenylethoxy)pentyl]amino]methyl]-1,3-benzenedimethanolhydrochloride

Example 50: 4-Hydroxy-α¹-[[[5-(3-phenylpropoxy)pentyl]amino]methyl]-1,3-benzenedimethanolhydrochloride

    ______________________________________                                        Ex-   Inter-    Chromatography eluents                                        ample mediate   EA-Methanol-NEt.sub.3                                                                         M.p. °C.                               ______________________________________                                        31    31         90:10:1*       81-82                                         32    32         85:15:1*       66-67                                         33    33        89:10:1         89-91                                         34    34        89:10:1         63-67                                         35    35        No chromatography                                                                             97-99                                         36    36 + KI   89:10:1         75-77                                         37    37 + KI   89:10:1         96-99                                         38    38        89:10:1         72-75                                         39    39        4:1:0*          68-70                                         40    40        89:10:1         76-78                                         41    +         79:20:1         69-70                                         42    41        89:10:1         79-81                                         43    45        3:1:0*          63-68                                         44    46        7:10:1          66-71                                         45    47        90:10:1         80-81                                         46    48        3:1:0*          75-78                                         47    49        3:1:0*          88.5-93.5                                     48    50        4:1:0*          75-78                                         49    51        3:1*            66-67                                                                         (hydrochloride)                               50    52        3:1*            50-56                                                                         (Hydrochloride)                               ______________________________________                                         *The silica was deactivated with NEt.sub.3                                    + [1[(6Bromohexyl)oxy]methyl]benzene                                     

EXAMPLE 51 4-Hydroxy-α¹-[[[5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol

A mixture of Intermediate 1 (1.15 g), DMF (10 ml),N,N-diisopropylethylamine (1.2 g) and Intermediate 53 (0.9 g) was heatedat 75° for 2 h. The mixture was diluted with H₂ O (150 ml) acidified topH4 with 2M hydrochloric acid, basified to pH8 with solid KHCO₃ andextracted with EA (2×80 ml). The extracts were washed with H₂ O (50 ml),BR (50 ml), dried (Na₂ SO₄) and evaporated in vacuo to give an oil whichwas purified by [FCTS] using EA-methanol-triethylamine (85:15:1) as theeluant to give the product as an oil. This was dissolved in warm EA (15ml) and cooled to give the title compound as an off-white solid (0.35 g)m.p. 117°-119°.

T.l.c. EN (EA-CH₃ OH 17:3) Rf 0.32.

EXAMPLE 52 4-Hydroxy-α¹-[[[6-[2-(4-methoxyphenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol

A mixture of Intermediate 1 (0.95 g), Intermediate 54 (1.50 g) and N,Ndiisopropylethylamine (1.35 ml) in DMF (molecular sieve dried, 11 ml)was heated at 80° for 1 h under nitrogen. The clear brown solution wasbasified with 8% NaHCO₃ solution (36 ml) and the cloudy mixture wasextracted with EA (3×110 ml). The combined organic extracts were washedconsecutively with H₂ O (110 ml) and BR (50 ml), dried (Na₂ SO₄) andevaporated. The resultant oil (2.43 g) was purified by [FCS] [I] to givea solid which, on trituration with ER (25 ml) gave the title compound asa white solid (0.582 g), m.p. 101°-102°.

Analysis Found: C,68.65;H,8.55;N,3.35. C₂₄ H₃₅ NO₅ requiresC,69.05;H,8.45;N,3.35%.

EXAMPLE 53 4-Hydroxy-α¹-[[[1-methyl-6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 4 (0.94 g) and Intermediate 55 (0.6 g) inethanol (40 ml) was hydrogenated over 10% palladium on charcoal (0.25 g)and 5% platinum on charcoal (0.25 g) for 20 h, filtered, and evaporated.The residue was purified on a column of silica (Merck 9385, 50 ml) [I]to give a colourless oil. Trituration of the oil with ER (10 ml) gavethe title compound as a white solid (0.3 g), m.p. 68°-76°. T.l.c. [M] Rf0.2.

EXAMPLE 54 4-Hydroxy-α¹-[[[1-methyl-6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 4 (1.39 g) and Intermediate 56 (1.0 g) inethanol (40 ml) was hydrogenated over 10% palladium on charcoal (0.2 g)and 5% platinum on charcoal (0.2 g) for 26 h, filtered and evaporated.The residue was purified on a column of silica (Merck 9385; 100 ml) [I]to give the title compound as a white solid (0.62 g) m.p. 57°-60°.T.l.c. [M] Rf 0.2.

EXAMPLE 55 4-Hydroxy-α¹-[[[1-methyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 4 (1.6 g) and Intermediate 58 (1.0 g) inethanol (60 ml) was hydrogenated over 10% palladium on charcoal (0.3 g)and 5% platinum on charcoal (0.3 g) for 20 h, filtered and evaporated.The residue was purified on a column of silica (Merck 9385; 90 ml) [I]to give a colourless oil. Trituration of the oil with ER (20 ml) gavethe title compound as a white solid (0.8 g) m.p. 86°-93°. T.l.c. [M] Rf0.25.

EXAMPLE 56 4-Hydroxy-α¹-[[[1-ethyl-6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 60 (1.0 g) and Intermediate 4 (2.19) inabsolute ethanol (60 ml) was hydrogenated over a mixture of palladium oncarbon catalyst (200 mg) and platinum on carbon catalyst (200 mg) at RTand atmospheric pressure. After 18 h, the mixture was filtered and thefiltrate evaporated in vacuo to give a yellow solid. Purification by[FCTS] (120 g) with EA-methanol-triethylamine (95:5:1) as eluant gavethe title compound as a white solid (480 mg) m.p. 82°-84°. T.l.c. EN(EA-methanol) (19:1) Rf 0.37.

EXAMPLE 57 4-Hydroxy-α¹-[[[1-methyl-5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 4 (1.45 g) and Intermediate 59 (1.0 g) inethanol (60 ml) was hydrogenated over 10% palladium on charcoal (0.3 g)and 5% platinum on charcoal (0.3 g) for 20 h, filtered and evaporated.The residue was purified on a column of silica (Merck 9385; 100 ml) [I]to give a colourless oil. Trituration of the oil with ER (20 ml) gavethe title compound as a white solid (0.9 g) m.p. 64°-66°. T.l.c. [M] Rf0.2.

EXAMPLE 58 4-Hydroxy-α¹-[[[5-(2-phenylethoxy)-1-propylpentyl]amino]methyl]-1,3-benzenedimethanolbenzoate salt

A solution of Intermediate 4 (2.77 g) and Intermediate 61 (2.0 g) inethanol (120 ml) was hydrogenated over 10% palladium on charcoal (0.25g) and 5% platinum on charcoal (0.45 g) for 22 h, filtered andevaporated. The residue was purified on a column of silica (Merck 9385;150 ml) eluted with EA-methanol-triethylamine (19:1:0.1) to give acolourless oil (0.5 g). The oil in CHCl₃ (5 ml) was added to benzoicacid (0.2 g) in CHCl₃ (5 ml) and the CHCl₃ was evaporated. The residuewas triturated with ER (3×25 ml) to give the title compound as a whitesolid (0.36 g) m.p. 67°-69°. T.l.c. [M] Rf 0.35.

EXAMPLE 59 α¹-[[[6-[2-(4-Fluorophenyl)ethoxy]-1-methylhexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

Intermediate 63 (623 mg) and Intermediate 4 (896 mg) in ethanol (20 ml)were hydrogenated over pre-reduced 5% platinum oxide-on-carbon (0.3 g)and 10%-palladium oxide-on-carbon (50% paste with H₂ O, 0.35 g) untiluptake of hydrogen ceased. The catalyst was removed by filtration(Hyflo) and the residue purified by [FCS] eluting withEA-methanol-triethylamine (94:5:1→89:10:1) to give, after triturationwith ER the title compound as a cream solid (652 mg) m.p. 60°-62°.

Analysis Found: C,68.75;H,8.45;N,3.25. C₂₄ H₃₄ FNO₄ requiresC,68.7;H,8.15;N,3.35%.

EXAMPLE 60 4-Hydroxy-α¹-[[[6-[3-(4-methoxyphenyl)propoxy]-1-methylhexyl]amino]methyl]-1,3-benzenedimethanol

A solution of Intermediate 65 (1.45 g) and Intermediate 1 (0.954 g) inacetic acid (0.311 g) and methanol (22 ml) was treated with sodiumcyanoborohydride (0.228 g) at RT. The mixture was stirred for 16 h, andpoured into 8% aqueous NaHCO₃ (30 ml) and extracted with EA (3×30 ml).The combined dried (Na₂ SO₄) extracts were evaporated to give an oil(1.06 g) which was purified by [FCS][I]. The resulting oil wastriturated with ER (25 ml) and evaporated to give the title compound asa white solid (0.713 g) m.p. 75°-77° . T.l.c. [I] Rf 0.19.

EXAMPLE 61 α¹-[[[1,1-Dimethyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol

A solution of Intermediate 67 (0.70 g) in ethanol (35 ml) washydrogenated over 5% platinum on charcoal (0.2 g) for 30 min, filteredand evaporated. The residue was triturated with CX-ER 9:1 to give thetitle compound as a white solid (0.51 g) m.p. 67°-69°. T.l.c. [M] Rf0.3.

EXAMPLE 62 α¹-[[[1,1-Dimethyl-6-(2-phenylethoxy)hexyl]amino]methyl-4-hydroxy-1,3-benzenedimethanol

A solution of methyl 5-(bromoacetyl)-2-hydroxybenzoate (2.2 g)Intermediate 70 (2.0 g) and N,N-diisopropyl ethylamine (1.16 g) in EA(40 ml) was refluxed for 3 h, filtered and evaporated. The residue in ER(50 ml) was filtered and the filtrate added dropwise to a suspension ofLiAlH₄ (1.6 g) to ER (100 ml) at 0°. The mixture was stirred at RT for 2h, treated cautiously with H₂ O (10 ml), acidified to pH1 withhydrochloric acid (2M), and basified to pH8 with solid K₂ CO₃. Theresulting slurry was extracted with CHCl₃ (4×200 ml) and the driedextract was evaporated. The residue was purified on a column of silica(Merck 9385; 150 ml) to give the title compound as a beige solid (0.3 g)m.p. 68°-71°. T.l.c. [M] Rf 0.2.

EXAMPLE 63 (R)-(-)-4-Hydroxy-α¹-[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol

Intermediate 77 (750 mg) was hydrogenated in absolute ethanol (60 ml)over pre-reduced 10% palladium oxide on carbon (50% paste, 150 mg).After 2 h, uptake of hydrogen (70 ml) ceased. The catalyst was removedby filtration through Hyflo and the filtrate was concentrated in vacuo.The crude product was purified by [FCS] using EA-methanol-triethylamine80:20:1 as eluant to give the title compound as a very viscous oil (270mg).

Specific Rotation T.l.c. (EA-methanol-triethylamine 80:20:1) Rf=0.22.

Analysis Found: C,71.44;H,8.34;N,3.40. C₂₄ H₃₅ NO₄ requiresC,71.79;H,8.79;N,3.49%.

EXAMPLE 64 4-Hydroxy-α¹-[[[6-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (a)1-[4-Hydoxy-3-(hydroxymethyl)phenyl]-2-[6-(3-phenylpropoxy)hexyl](phenylmethyl)amino]ethanone

N,N-Diisopropylethylamine (2.77 g) in CH₂ Cl₂ (5 ml) was added to astirred suspension of2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (2.5 g) andIntermediate 22 (4.15 g) in CH₂ Cl₂ (30 ml). The solution was kept at23° for 24 h, washed with H₂ O (5×17.5 ml) and evaporated in vacuo togive the crude product (a) as an oil. T.l.c. (isopropyl acetate:lightpetroleum, b.p. 60°-80°, 1:1) Rf 0.4.

(b) 4-Hydroxy-α¹-[[[6-(3-phenylpropoxy)hexyl]amino]methyl-1,3-benzenedimethanol

A solution of the crude product (a) in absolute ethanol (120 ml) washydrogenated at 40° and atmospheric pressure over 10% palladium oncarbon (0.1 g) and 10% platinum on carbon (0.1 g) catalysts. The mixturewas filtered through Hyflo and evaporated to give an oil. The oil wasdissolved in EA, the solution evaporated under reduced pressure and theresidual oil was triturated with EA (5 ml) to give the title compound asa white solid m.p. 81°-82.5°. T.l.c. (EA:CH₃ OH:NH₃ 30:10:1) Rf 0.35.

The stimulant action at β₂ -adrenoreceptors of compounds of theinvention was determined using the following:

GUINEA-PIG TRACHEAL STRIP PREPARATION

Tracheal rings were mounted in a superfusion apparatus, and continuouslysuperfused with oxygenated physiological (Kreb's) solution containingindomethacin (2.4×10⁻⁶ M) and atropine (4×10⁻⁷ M) at 37° at a rate of 2ml/min. Changes in tension of the preparation were measured using anisometric strain gauge. Preparations were contracted for the duration ofthe test by the inclusion of prostaglandin F₂ α (2.9×10⁻⁶ M) in thesuperfusion fluid. Two bolus dose-effect curves to the standard,isoprenaline, (1×10⁻¹² -1×10⁻⁹ moles) were obtained at the start of eachtest in a cumulative fashion, allowing the relaxation obtained with eachto reach its own maximum before the next increment was made. Oncompletion of this dose-effect curve, sufficient time was allowed forthe tissue to recover (15-30 min). After this time, sequentialconcentration-effect curves were constructed for first isoprenaline andthen the test compound. These were constructed as follows: a lowconcentration (isoprenaline 3×10⁻¹⁰ M; test compound 1×10⁻¹⁰ M) wasinfused until any response obtained had reached its maximum, then theinfusion was stopped and the tissue allowed to recover for a maximum of30 min. After this period the procedure was repeated using progressivelyincreasing concentrations of agonist, and in this way, wholeconcentration-effect curves obtained. Potency was determined bycomparison of the concentration-effect curve thus constructed with thatpreviously obtained for isoprenaline and expressed as equipotentconcentration (isoprenaline=1) i.e. ##EQU1## was calculated.

Duration of action was also measured for each response, and is the timetaken from stopping the infusion to 50% recovery. Graphs were drawn forduration times against response magnitude, and from these, durationtimes for 50% maximum responses were determined.

The ability of compounds of the invention to afford protection againsthistamine-induced bronchoconstriction was demonstrated using thefollowing:

CONSCIOUS GUINEA PIG TEST

The principal of the method is that bronchoconstriction leads to adecrease in tidal volume, and hence to an increase in respiratory rate.Guinea pigs were placed in a whole body plesythmograph i.e. a chamberseparated, by means of a collar, into 2 parts-a head chamber and a bodychamber. Pressure changes in the body chamber were monitored by means ofa low pressure transducer, from which was derived a continuous, linearrecording of respiratory rate by means of an instantaneous ratemeterconnected to a chart recorder. The head chamber was connected to anexpansion chamber into which a histamine aerosol was driven from asolution of set concentration (usually 5 mg/ml) for a predeterminedperiod (usually 10-15 seconds). At the end of this period, the aerosolwas switched off, but the guinea pig was left in contact with theaerosolized histamine still in the expansion chamber until hisrespiratory rate increased by 40%, or for a total of 4 min, whicheverwas the sooner. The degree of bronchoconstriction was expressed in termsof the area under the respiratory rate curve. Guinea-pigs werechallenged at intervals until their rate responses were constant, thenthey were given a dose of the test compound by either aerosol or oralroute, and the response to histamine reassessed first at 30 min postdose, and then at intervals thereafter for up to 24 h post dose. Bytesting a range of doses of the test compound, a dose-relationship inthe maximum protection was determined, and the time taken (up to 24 h)for the response to histamine challenge to return to pre-test compoundprotection levels determined. Each dose of each test compound was testedin at least 4 animals.

PHARMACEUTICAL EXAMPLES Tablets

These may be prepared by the normal methods such as wet granulation ordirect compression.

A. Direct Compression

    ______________________________________                                                           mg/tablet                                                  ______________________________________                                        Active ingredient    2.0                                                      Microcrystalline Cellulose USP                                                                     196.5                                                    Magnesium Stearate BP                                                                              1.5                                                      Compression weight   200.0                                                    ______________________________________                                    

The active ingredient is sieved through a suitable sieve, blended withthe excipients and compressed using 7 mm diameter punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to microcrystalline cellulose or the compressionweight and using punches to suit.

B. Wet Granulation

    ______________________________________                                                           mg/tablet                                                  ______________________________________                                        Active ingredient    2.0                                                      Lactose BP           151.5                                                    Starch BP            30.0                                                     Pregelatinised Maize Starch BP                                                                     15.0                                                     Magnesium Stearate BP                                                                              1.5                                                      Compression weight   200.0                                                    ______________________________________                                    

The active ingredient is sieved through a suitable sieve and blendedwith lactose, starch and pregelatinised maize starch. Suitable volumesof purified water are added and the powders are granulated. Afterdrying, the granules are screened and blended with the magnesiumstearate. The granules are then compressed into tablets using 7 mmdiameter punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to lactose or the compression weight and using punchesto suit.

C. For Buccal administration

    ______________________________________                                                           mg/tablet                                                  ______________________________________                                        Active ingredient    2.0                                                      Lactose BP           94.8                                                     Sucrose BP           86.7                                                     Hydroxypropylmethylcellulose                                                                       15.0                                                     Magnesium Stearate BP                                                                              1.5                                                      Compression weight   200.0                                                    ______________________________________                                    

The active ingredient is sieved through a suitable sieve and blendedwith the lactose, sucrose and hydroxypropylmethylcellulose. Suitablevolumes of purified water are added and the powders are granulated.After drying, the granules are screened and blended with the magnesiumstearate. The granules are then compressed into tablets using suitablepunches.

The tablets may be film coated with suitable film forming materials,such as hydroxypropyl methylcellulose, using standard techniques.Alternatively the tablets may be sugar coated.

Capsules

    ______________________________________                                                        mg/capsule                                                    ______________________________________                                        Active ingredient 2.0                                                         *Starch 1500      97.0                                                        Magnesium Stearate BP                                                                           1.0                                                         Fill Weight       100.0                                                       ______________________________________                                         *A form of directly compressible starch.                                 

The active ingredient is sieved and blended with the excipients. The mixis filled into size No. 2 hard gelatin capsules using suitablemachinery. Other doses may be prepared by altering the fill weight andif necessary changing the capsule size to suit.

Syrup

This may be either a surcose or sucrose free presentation.

A. Sucrose Syrup

    ______________________________________                                                          mg/5 ml dose                                                ______________________________________                                        Active ingredient         2.0                                                 Sucrose BP              2750.0                                                Glycerine BP             500.0                                                Buffer                                                                        Flavour                                                                       Colour                  as required                                           Preservative                                                                  Purified water BP to      5.0 ml                                              ______________________________________                                    

The active ingredient, buffer, flavour, colour and preservative aredissolved in some of the water and the glycerine is added. The remainderof the water is heated to dissolve the sucrose and is then cooled. Thetwo solutions are combined, adjusted to volume and mixed. The syrupproduced is clarified by filtration.

B. Sucrose-Free

    ______________________________________                                                              mg/5 ml dose                                            ______________________________________                                        Active ingredient            2.0 mg                                           Hydroxypropyl methylcellulose USP                                                                         22.5 mg                                           (viscosity type 4000)                                                         Buffer                                                                        Flavour                                                                       Colour                      as required                                       Preservative                                                                  Sweetner                                                                      Purified Water BP to         5.0 ml                                           ______________________________________                                    

The hydroxypropyl methylcellulose is dispersed in hot water, cooled andthen mixed with an aqueous solution containing the active ingredient andthe other components of the formulation. The resultant solution isadjusted to volume and mixed. The syrup produced is clarified byfiltration.

Suppositories

    ______________________________________                                        Active ingredient      2.0 mg                                                 *Witepsol H15 to       1.0 g                                                  ______________________________________                                         *A proprietary grade of Adeps Solidus Ph. Eur.                           

A suspension of the active ingredient in molten Witepsol is prepared andfilled, using suitable machinery, into 1 g size suppository moulds.

Injection for Intravenous Administration

    ______________________________________                                                         mg/ml                                                        ______________________________________                                        Active ingredient  0.5 mg                                                     Sodium Chloride BP as required                                                Water for Injection BP to                                                                        1.0 ml                                                     ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted, using acid or alkali, to that of optimumstability and/or facilitate solution of the active ingredient.Alternatively suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate sizeampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen or other suitable gas.

Inhalation Cartridges

    ______________________________________                                                         mg/cartridge                                                 ______________________________________                                        Active ingredient micronised                                                                     0.200                                                      Lactose BP to      25.0                                                       ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range prior to blending with normal tabletting gradelactose in a high energy mixer. The powder blend is filled into No. 3hard gelatin capsules on a suitable encapsulating machine. The contentsof the cartridges are administered using a powder inhaler such as theGlaxo Rotahaler.

Metered Dose Pressurised Aerosol A. Suspension Aerosol

    ______________________________________                                                      mg/metered dose                                                                            Per can                                            ______________________________________                                        Active ingredient micronised                                                                  0.100          26.40 mg                                       Oleic Acid BP   0.010           2.64 mg                                       Trichlorofluoromethane BP                                                                     23.64           5.67 g                                        Dichlorodifluoromethane BP                                                                    61.25          14.70 g                                        ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range. The Oleic Acid is mixed with theTrichlorofluoromethane at a temperature of 10°-15° C. and the microniseddrug is mixed into the solution with a high shear mixer. The suspensionis metered into aluminium aerosol cans and suitable metering valves,delivering 85 mg of suspension are crimped onto the cans and theDichlorodifluoromethane is pressure filled into the cans through thevalves.

B. Solution Aerosol

    ______________________________________                                                      mg/metered dose                                                                            Per can                                            ______________________________________                                        Active ingredient                                                                             0.100          24.0 mg                                        Ethanol BP      7.500           1.80 g                                        Trichlorofluoromethane BP                                                                     18.875          4.53 g                                        Dichlorodifluoromethane BP                                                                    48.525         11.65 g                                        ______________________________________                                    

Oleic acid BP, or a suitable surfactant e.g. Span 85 (sorbitantrioleate) may also be included.

The active ingredient is dissolved in the ethanol together with theoleic acid or surfactant if used. The alcoholic solution is metered intosuitable aerosol containers followed by the trichlorofluoromethane.Suitable metering valves are crimped onto the containers anddichlorodifluoromethane is pressure filled into them through the valves.

`Active Ingredient` is used in the above examples to represent acompound of the invention, and can be, for example, the compound ofExample 2.

We claim:
 1. A method of treating a patient suffering from a diseaseassociated with reversible airways obstruction which comprisesadministering to the patient an effective amount of a compound ofgeneral formula (I) ##STR33## wherein m is an integer from 2 to 8 andnis an integer from 1 to 7 with the proviso that the sum total of m+n is4 to 12; Ar represents a phenyl group which may be unsubstituted orsubstituted by one or two substituents selected from halogen atoms, C₁₋₃alkyl and C₁₋₃ alkoxy groups, or by an alkylenedioxy group of formula--O(CH₂)_(p) O-- where p is 1 or 2; and R¹ and R², which may be the sameor different, each represents a hydrogen atom or a C₁₋₃ alkyl group withthe proviso that the sum total of carbon atoms in R¹ and R² is not morethan 4;or a physiologically acceptable salt or solvate thereof.
 2. Amethod according to claim 1, wherein m is 3 and n is 6; or m is 4 and nis 3, 4 or 5; or m is 5 and n is 2, 3, 4 or 5; or m is 6 and n is 2 or3.
 3. A method according to claim 1, wherein the sum total of m+n is 7,8, 9 or
 10. 4. A method according to claim 1, wherein R¹ and R², whichmay be the same or different, each represents a hydrogen atom or amethyl group.
 5. A method according to claim 1, Ar represents anunsubstituted phenyl group or a phenyl group substituted by onesubstituent selected from chlorine and fluorine atoms, methoxy andmethyl groups.
 6. A method according to claim 1, comprisingadministering an effective amount of a compound of the general formula(Ia): ##STR34## wherein m is an integer from 3 to 6 andn is an integerfrom 2 to 6 with the proviso that the sum total of m+n is 7 to 10inclusive; and Ar is phenyl or phenyl substituted by a methyl or methoxygroup or a fluorine or chlorine atom; or the physiologically acceptablesalts and solvates thereof.
 7. A method according to claim 6, wherein R¹is a hydrogen atom and R² is a hydrogen atom or a methyl group.
 8. Amethod according to claim 6, wherein R¹ and R², which may be the same ordifferent is each a hydrogen atom or a methyl group, m is 4 or 5, n is2, 3 or 4 and Ar is phenyl or phenyl substituted by a chlorine orfluorine atom or a methoxy or methyl group.
 9. A method according toclaim 1, wherein the compound is selected from the group consistingof4-hydroxy-α¹-[[[6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[5-(4-phenylbutoxy)pentyl]amino]-methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-methyl-6-(2-phenylethoxy)hexyl]-amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-methyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-1,3-benzenedimethanol4-hydroxy-α¹-[[[1-methyl-5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-ethyl-6-(2-phenylethoxy)hexyl]-amino]methyl]-1,3-benzenedimethanol;α¹-[[[1,1-dimethyl-6-(2-phenylethoxy)hexyl]amino]-methyl-4-hydroxy-1,3-benzenedimethanol;α¹-[[[6-[2-(4-fluorophenyl)ethoxy]-1-methylhexyl]-amino]methyl]-4-hydroxy-1,3-benzenedimethanol;4-hydroxy-α¹-[[[6-[3-(4-methoxyphenyl)propoxy]-1methylhexyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-methyl-6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[6-[2-(4-methylphenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol;α¹-[[[6-[2-(3-chlorophenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol;4-hydroxy-α¹-[[[6-[2-(4-methoxyphenyl)ethoxy]hexyl]amino]-methyl]-1,3-benzenedimethanol;α¹-[[[6-[3-(4-fluorophenyl)propoxy]hexyl]amino]-methyl]-4-hydroxy-1,3-benzenedimethanol;orthe physiologically acceptable salts thereof.
 10. A method according toclaim 1, wherein the disease is asthma or chronic bronchitis.
 11. Amethod of treating a patient suffering from an inflammatory or allergicskin disease, or a condition in which there is an advantage in loweringgastric acidity which method comprises administering to the patient aneffective amount of a compound of general formula (I) ##STR35## whereinm is an integer from 2 to 8 andn is an integer from 1 to 7 with theproviso that the sum total of m+n is 4 to 12; Ar represents a phenylgroup which may be unsubstituted or substituted by one or twosubstituents selected from halogen atoms, C₁₋₃ alkyl and C₁₋₃ alkoxygroups, or by an alkylenedioxy group of formula --O(CH₂)_(p) O-- where pis 1 or 2; and R¹ and R², which may be the same or different, eachrepresents a hydrogen atom or a C₁₋₃ alkyl group with the proviso thatthe sum total of carbon atoms in R¹ and R² is not more than 4;or aphysiologically acceptable salt or solvate thereof.
 12. A methodaccording to claim 11, wherein m is 3 and n is 6; or m is 4 and n is 3,4 or 5; or m is 5 and n is 2, 3, 4 or 5; or m is 6 and n is 2 or
 3. 13.A method according to claim 11, wherein the sum total of m+n is 7, 8, 9or
 10. 14. A method according to claim 11, wherein R¹ and R¹, which maybe the same or different, each represents a hydrogen atom or a methylgroup.
 15. A method according to claim 11, wherein Ar represents anunsubstituted phenyl group or a phenyl group substituted by onesubstituent selected from chlorine and fluorine atoms, methoxy andmethyl groups.
 16. A method according to claim 11, comprisingadministering a compound of the general formula (Ia): ##STR36## whereinm is an integer from 3 to 6 andn is an integer from 2 to 6 with theproviso that the sum total of m+n is 7 to 10 inclusive; and Ar is phenylor phenyl substituted by a methyl or methoxy group or a fluorine orchlorine atom; or the physiologically acceptable salts and solvatesthereof.
 17. A method according to claim 16, wherein R¹ is a hydrogenatom and R² is a hydrogen atom or a methyl group.
 18. A method accordingto claim 16, wherein R¹ and R², which may be the same or different iseach a hydrogen atom or a methyl group, m is 4 or 5, n is 2, 3 or 4 andAr is phenyl or phenyl substituted by a chlorine or fluorine atom or amethoxy or methyl group.
 19. A method according to claim 11, wherein thecompound is selected from the group consisting of4-hydroxy-α¹-[[[6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[5-(4-phenylbutoxy)pentyl]amino]-methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-methyl-6-(2-phenylethoxy)hexyl]-amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-methyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-methyl-5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[1-ethyl-6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;α¹-[[[1,1-dimethyl-6-(2-phenylethoxy)hexyl]amino]-methyl-4-hydroxy-1,3-benzenedimethanol;α¹-[[[6-[2-(4-fluorophenyl)ethoxy]-1-methylhexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol;4-hydroxy-α¹ -[[[6-[3-(4-methoxyphenyl)propoxy]-1-methylhexyl]amino]methyl]-1,3-benzenedimethanol; 4-hydroxy-α¹-[[[1-methyl-6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;4-hydroxy-α¹-[[[6-[2-(4-methylphenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol;α¹-[[[6-[2-(3-chlorophenyl)ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol;4-hydroxy-α¹-[[[6-[2-(4-methoxyphenyl)ethoxy]hexyl]amino]-methyl]-1,3-benzenedimethanol;α¹-[[[6-[3-(4-fluorophenyl)propoxy]hexyl]amino]-methyl]-4-hydroxy-1,3-benzenedimethanol;orthe physiologically acceptable salts thereof.
 20. A method according toclaim 11, wherein the patient is suffering from gastric or pepticulceration.
 21. A method according to claim 11, wherein the patienttreated is suffering from psoriasis.